8 Beta-hydrocarbyl-substituted estratrienes for use as selective estrogens

ABSTRACT

This invention describes the new 8β-substituted estratrienes of general formula I in which R 2 , R 3 , R 6 , R 6′ , R 7 , R 7′ , R 9 , R 11 , R 11′ , R 12 , R 14 , R 15 , R 15′ , R 16 , R 16′ , R 17  and R 17′  have the meanings that are indicated in the description, and R 8  means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical, as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations of rat prostates than to estrogen receptor preparations of rat uteri and in vivo preferably a preferential action on bone rather than the uterus and/or a pronounced action with respect to stimulation of the expression of 5HT2a-receptors and 5HT2a-transporters, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for treatment of estrogen-deficiency-induced diseases and conditions as well as the use of an 8β-substituted estratriene structural part in the total structures of compounds that have a dissociation in favor of their estrogenic action on bones rather than the uterus.

FIELD OF THE INVENTION

[0001] This invention relates to new compounds as pharmaceutical activeingredients, which have in vitro a higher affinity to estrogen receptorpreparations from rat prostates than to estrogen receptor preparationsfrom rat uteri and in vivo a preferential action on bone rather than theuterus and/or a pronounced action with respect to stimulation of theexpression of 5HT2a-receptors and 5HT2a-transporters, their production,their therapeutic use and pharmaceutical dispensing forms that containthe new compounds. The chemical compounds are novel, steroidal,tissue-selective estrogens.

BACKGROUND OF THE INVENTION

[0002] Established estrogen therapies for treatment ofhormone-deficiency-induced symptoms and the protective action ofestrogens on bones, brains, vessels and other organ systems.

[0003] The efficiency of estrogens in the treatment ofhormone-deficiency-induced symptoms such as hot flashes, atrophy ofestrogen target organs and incontinence, as well as the successful useof estrogen therapies for prevention of bone mass loss in peri- andpostmenopausal women, is well documented and generally accepted (Gradyet al. 1992, Ann Intern Med 117: 1016-1037). It is also well documentedthat estrogen replacement therapy in postmenopausal women or in womenwith ovarian dysfunction that is caused in some other way reduces therisk of cardiovascular diseases compared to non-estrogen-treated women(Grady et al., loc. cit.).

[0004] In addition, more recent studies confirm a protective action ofestrogens against neurodegenerative diseases, such as, e.g., Alzheimer'sdisease (Henderson 1997, Neurology 48 (Suppl 7): pp. 27-35; Birge 1997,Neurology 48 (Suppl 7): pp.36-41), a protective action with respect tobrain functions, such as memory and learning capacity (McEwen et al.1997, Neurology 48 (Suppl 7): pp. 8-15; Sherwin 1997, Neurology 48(Suppl 7): pp. 21-26), as well as against hormone-deficiency-inducedmood swings (Halbreich 1997, Neurology 48 (Suppl 7): pp. 16-20).

[0005] In addition, estrogen replacement therapy has proven effectiverelative to the reduction of the incidence of colorectal carcinoma(Calle, E. F. et al., 1995, J Natl Cancer Inst 87: 517-523).

[0006] In conventional estrogen or hormone replacement therapy (=HRT),natural estrogens, such as estradiol, and conjugated estrogens thatconsist of equine urine are used either by themselves or in combinationwith a gestagen. Instead of the natural estrogens, derivatives that areobtained by esterification, such as, e.g., 17β-estradiol-valerate, canalso be used.

[0007] Because of the stimulating action of the estrogens that are usedon the endometrium, which results in an increase of the risk ofendometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166:1986-1992), estrogen/gestagen combination preparations are preferablyused in hormone replacement therapy. The gestagenic component in theestrogen/gestagen combination avoids hypertrophy of the endometrium, butthe occurrence of undesirable intracyclic menstrual bleeding is alsolinked to the gestagen-containing combination.

[0008] Selective estrogens represent a more recent alternative to theestrogen/gestagen combination preparations. Up until now, selectiveestrogens have been defined as those compounds that have anestrogen-like effect on the brain, bones and vascular system, owing totheir antiuterotrophic (i.e., antiestrogenic) partial action, but theydo not have a proliferative effect on the endometrium.

[0009] A class of substances that partially meet the desired profile ofa selective estrogen are the so-called “Selective Estrogen ReceptorModulators” (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9):531-539). In this case, these are partial agonists of estrogen receptorsubtype “ERα.” This substance type is ineffective, however, with respectto the therapy of acute postmenopausal symptoms, such as, e.g., hotflashes. As an example of a SERM, the raloxifene that was recentlyintroduced for the indication of osteoporosis can be mentioned.

[0010] Estrogen Receptor Beta (ERβ)

[0011] Estrogen receptor β (ERβ) was recently discovered as a secondsubtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl.Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). Theexpression pattern of ERβ differs from that of the ERα (Kuiper et al.(1996), Endocrinology 138: 863-870). ERβ thus predominates over ERα inthe rat prostate, while ERα predominates over ERβ in the rat uterus.Areas in which in each case only one of the two ER-subtypes is expressedwere identified in the brain (Shugrue et al. (1996), Steroids 61:678-681; Li et al. (1997), Neuroendocrinology 66:63-67). ERβ isexpressed in, i.a., areas that are considered to be important forcognitive processes and “mood” (Shugrue et al. 1997, J ComparativeNeurology 388: 507-525).

[0012] Molecular targets for ERG in these brain areas could be the5HT2a-receptor and the serotonin transporter (G. Fink & B. E. H. Sumner1996 Nature 383:306; B. E. H. Sumner et al. 1999 Molecular BrainResearch, in press). The neurotransmitter serotonin(5-hydroxytryptamine) is involved in the regulation of a considerablenumber of processes, which can be impaired in menopause. In particular,the effects of menopause on emotion and cognition are connected with theserotoninergic system. Estrogen replacement therapy has proven effectivewith respect to treatment of these estrogen deficiency-producedsymptoms, possibly by modulation of serotonin receptor and transporterexpression.

[0013] Other organ systems with comparatively higher ERβ-expressionencompass the bones (Onoe, Y. et al., 1997, Endocrinology 138:4509-4512), the vascular system (Register, T. C., Adams, M. R. 1998, J.Steroid Molec Biol 64: 187-191), the urogenital tract (Kuiper, G. J. M.et al. 1997, Endocrinology 138: 863-870), the gastrointestinal tract(Campbell-Thopson 1997, BBRC 240: 478-483), as well as the testis(Mosselmann, S. et al. 1996 Febs Lett 392 49-53) including thespermatides (Shugrue et al. 1998, Steroids 63: 498-504). The tissuedistribution suggests that estrogens regulate organ functions via ERβ.The fact that ERβ is functional in this respect also follows by studiesin ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bonemass loss in ERKO-mice, which can be cancelled out by estrogensubstitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine SocietyMeeting New Orleans). Estradiol in the blood vessels of female ERKO micealso inhibits vascular media and smooth muscle cell proliferation(Iafrati, M. D. et al. 1997, Nature Medicine 3: 545-548). Theseprotective actions of estradiol are carried out in the ERKO mousepresumably via ERβ.

[0014] Observations of βERKO mice provide an indication on a function ofERβ in the prostate and bladder: in the case of older male mice,symptoms of prostate and bladder hyperplasia occur (Krege, J. H. et al.1998, Proc Natl Acad Sci 95: 15677-15682). In addition, female ERKO mice(Lubahn, D. B. et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and maleERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well asfemale βERKO mice (Krege, J. H., 1998) have fertility disorders.Consequently, the important function of estrogens with respect tomaintaining testis and ovary functions as well as fertility isconfirmed.

[0015] It was possible to achieve a selective estrogen action onspecific target organs by subtype-specific ligands based on thedifferent tissue or organ distribution of the two subtypes of the ERs.Substances with a preference for ERβ compared to ERα in the in vitroreceptor binding test were described by Kuiper et al. (Kuiper et al.(1996), Endocrinology 138: 863-870). A selective action ofsubtype-specific ligands of the estrogen receptor on estrogen-sensitiveparameters in vivo was not previously shown.

[0016] The object of this invention is therefore to prepare compoundsthat have in vitro a dissociation with respect to the binding toestrogen receptor preparations from rat prostates and rat uteri and thathave in vivo a dissociation with respect to bones rather than the uterusaction. The compounds are to have in vitro a higher affinity to estrogenreceptor preparations from rat prostates than to estrogen receptorpreparations from rat uteri and in vivo a higher potency with respect toprotection against hormone-deficiency-induced bone mass loss incomparison to uterus-stimulating action in the uterus and/or pronouncedaction with respect to stimulation of the expression of 5HT2a-receptorsand 5HT2a-transporters.

[0017] In the broader sense, a structure-action relationship, whichallows for access to compounds that have the above-formulatedpharmacological profile of better estrogenic action on bones than on theuterus, is to be made available by this invention.

[0018] According to the invention, the object above is achieved by theprovision of 8β-substituted estra-1,3,5(10)-triene derivatives ofgeneral formula I′

[0019] in which

[0020] R² means a hydrogen atom, a halogen atom;

[0021] a radical R¹⁸— or R¹⁸—O—, whereby R¹⁸ means a hydrogen atom or astraight-chain or branched-chain, saturated or unsaturated hydrocarbonradical with up to 6 carbon atoms, a trifluoromethyl group;

[0022] a group R¹⁹SO₂—O—, in which R¹⁹ is an R²⁰R²¹N group, whereby R²⁰and R²¹, independently of one another, mean a hydrogen atom, aC₁-C₅-alkyl radical, a group C(O)R²², in which R²² represents anoptionally substituted, straight-chain or branched-chain, saturated orunsaturated in up to three places, optionally partially or completelyhalogenated hydrocarbon radical with up to 10 carbon atoms, anoptionally substituted C₃-C₇-cycloalkyl radical, an optionallysubstituted C₄-C₁₅-cycloalkylalkyl radical or an optionally substitutedaryl, heteroaryl or aralkyl radical, or, together with the N-atom, meansa polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;

[0023] R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹and R²² in each case in the meaning that is indicated under R², wherebyin addition an aryl, heteroaryl or aralkyl radical can stand for R¹⁸;

[0024] R⁶ and R⁷ each mean a hydrogen atom or together an additionalbond;

[0025] R^(6′) and R^(7′), independently of one another, mean a hydrogenatom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹and R²² in each case in the meaning that is indicated under R²;

[0026] R⁸ means a straight-chain or branched-chain, optionally partiallyor completely halogenated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl or prop-1-inyl radical;

[0027] R⁹ means a hydrogen atom, a straight-chain or branched-chain,saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms,or together with R¹¹ means an additional bond;

[0028] R¹¹ means a hydrogen atom or together with R⁹ or together withR¹² means an additional bond;

[0029] R^(11′) means a hydrogen atom, a halogen atom, a saturated orunsaturated, optionally partially or completely halogenated (F, Cl)hydrocarbon radical, which has a maximum linear chain length of 4 carbonatoms, or a group —X—R^(18′), in which X is an oxygen or sulfur atom,and R^(18′)is an alkyl radical with 1 to 3 carbon atoms;

[0030] R¹² means a hydrogen atom or together with R¹¹ means anadditional bond;

[0031] R¹⁴ means a hydrogen atom or together with R¹⁵ means anadditional bond;

[0032] R¹⁵ means a hydrogen atom or together with R¹⁴ or together withR¹⁶ means an additional bond;

[0033] R¹⁶ means a hydrogen atom or together with R¹⁵ means anadditional bond;

[0034] R^(15′) and R^(16′), independently of one another, mean ahydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², withR¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²;

[0035] R¹⁷ and R^(17′) each mean a hydrogen atom; a hydrogen atom and ahalogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom anda group R¹⁹SO₂—O—;

[0036] a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O—and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all abovecases with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; or

[0037] R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ andR²⁴, independently of one another, represent a hydrogen atom and ahalogen atom, or together an oxygen atom;

[0038] for treatment of estrogen-deficiency-induced diseases andconditions.

[0039] The possible substituents at carbon atoms 6, 7, 9, 11, 15, 16 and17 can be respectively in α- or β-position.

[0040] According to a variant of the invention, preferably compounds ofgeneral formula I′ are used,

[0041] in which

[0042] R² means a hydrogen or halogen atom or a hydroxy group;

[0043] R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹and R²² in each case in the meaning that is indicated under R², wherebyin addition an aryl or aralkyl radical can stand for R¹⁸;

[0044] R⁶ and R⁷ each mean a hydrogen atom;

[0045] R^(6′) means a hydrogen atom, a hydroxy group, a group R²² in themeaning that is indicated under R²;

[0046] R^(7′) means a hydrogen atom, a halogen atom, a group R¹⁸—O—,R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case in the meaningthat is indicated under R²;

[0047] R⁸ means a straight-chain or branched-chain, optionally partiallyor completely halogenated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl- or prop-1-inyl radical;

[0048] R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

[0049] R¹¹ means a hydrogen atom or together with R⁹ an additional bond;

[0050] R^(11′) means a hydrogen atom, a halogen atom, a saturated orunsaturated, optionally partially or completely halogenated (F, Cl)hydrocarbon radical, which has a maximum linear chain length of 4 carbonatoms, or a group —X—R^(18′), in which X is a sulfur atom, and R^(18′),is an alkyl radical with 1 to 3 carbon atoms;

[0051] R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

[0052] R^(16′) means a hydrogen atom, a halogen atom, a group R¹⁸—O—,R¹⁹SO₂—O— or —R²², with R¹⁸,

[0053] R¹⁹, and R²² in each case in the meaning that is indicated underR²;

[0054] R¹⁷ and R^(17′) in each case mean a hydrogen atom; a hydrogenatom and a halogen atom; a hydrogen atom and a benzyloxy group; ahydrogen atom and a group R¹⁹SO₂—O—;

[0055] a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O—and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all abovecases with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; and

[0056] R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ andR²⁴, independently of one another, represent a hydrogen atom and ahalogen atom, or together an oxygen atom.

[0057] Another preferred variant of this invention calls for the use ofthose compounds of general formula I′,

[0058] in which

[0059] R² means a hydrogen atom or a fluorine atom or a hydroxy group,

[0060] R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹,and R²² in each case in the meaning that is indicated under R², wherebyin addition an aryl or aralkyl radical can stand for R¹⁸;

[0061] R⁶ and R⁷ in each case mean a hydrogen atom;

[0062] R^(6′) means a hydrogen atom or a hydroxy group,

[0063] R^(7′) means a hydrogen atom, a fluorine or chlorine atom, agroup R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in each case inthe meaning that is indicated under R²;

[0064] R⁸ means a straight-chain or branched-chain, optionally partiallyor completely fluorinated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl radical or prop-1-inyl radical;

[0065] R⁹, independently of one another, mean a hydrogen atom ortogether with R¹¹ an additional bond;

[0066] R^(11′) means a hydrogen atom, a fluorine or chlorine atom, asaturated, straight-chain or branched-chain C₁-C₄-alkyl group, a group—X—R^(18′), in which X is a sulfur atom and R^(18′) means a saturated,straight-chain or branched-chain C₁-C₃-alkyl group, a chloromethyl orchloroethyl group;

[0067] R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

[0068] R^(16′) means a hydrogen atom, a fluorine or chlorine atom or agroup R¹⁸—O— or —R²², with R¹⁸ and R²² in each case in the meaning thatis indicated under R²;

[0069] R¹⁷ and R^(17′) in each case mean a hydrogen atom; a hydrogenatom and a halogen atom; a hydrogen atom and a benzyloxy group; ahydrogen atom and a group R¹⁹SO₂—O—;

[0070] a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O—and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all abovecases with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; or

[0071] R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴, in which R²³ andR²⁴, independently of one another, represent a hydrogen atom and ahalogen atom, or together an oxygen atom.

[0072] According to another variant, 8β-substitutedestra-1,3,5(10)-triene derivatives of general formula I′ are used

[0073] in which

[0074] R^(6′), R^(7′), R⁹, R¹¹, R¹⁴, R¹⁵, R^(15′) and R¹⁶ in each casestand for a hydrogen atom, or R^(6′), R^(7′), R¹⁴, R¹⁵, R^(15′) and R¹⁶in each case stand for a hydrogen atom, and R⁹ and R¹¹ together standfor an additional bond, and all other substituents have the meaningsthat are indicated in claim 1.

[0075] If the estratriene derivatives of general formula I′ containadditional double bonds in the B-, C- and/or D-ring, then a double bondis preferably in position 9(11), 14(15) or 15(16) or two double bondsare present in positions 9(11) and 14(15) or 15(16).

[0076] Another variant of the invention are estratriene derivatives ofgeneral formula I′

[0077] in which

[0078] R¹⁷ and R^(17′) are a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—and a group —0—C(O)R²², with R¹⁸ and R²² in each case in the meaningthat is indicated under R².

[0079] Of the last-mentioned, in turn those gonatriene derivatives arepreferred in which

[0080] R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, aC₁-C₄-alkyl group or C₂-C₄-alkenyl group

[0081] and especially preferred are those in which

[0082] R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, amethyl, ethinyl or prop-1-inyl group.

[0083] Finally, an embodiment exists in that R^(16′) stands for a groupR¹⁸—O— or R¹⁹SO₂—O— with R¹⁸ and R¹⁹ in each case in the meaning that isindicated under R²; R¹⁷ and R^(17′) each stand for a hydrogen atom andall other substituents can have the meanings that are indicated ingeneral formula I′.

[0084] Preferred according to this invention is the use of one or moreof the following compounds:

[0085] 8β-Methyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol

[0086] 3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol

[0087] 8β-methyl-estra-1,3,5(10)-triene-3,17β-diol

[0088] 3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol

[0089] 8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol

[0090] 3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol

[0091]8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol

[0092]8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol

[0093] 8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0094] 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol

[0095] 8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol

[0096] 8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol

[0097] 8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol

[0098] 8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol

[0099] 8β-vinyl-estradiol-3-sulfamate

[0100] 8β-vinyl-estradiol-3,17-disulfamate

[0101] 8β-vinyl-estradiol-3-(N-acetyl)-sulfamate

[0102] 8β-vinyl-estrone-3-sulfamate

[0103] 8β-vinyl-estron-3-acetate

[0104] 8β-vinyl-estriol

[0105] 8β-vinyl-estriol-3-sulfamate

[0106] 8β-methyl-estrone-3-sulfamate

[0107] 8β-methyl-estriol

[0108] 8β-(prop-(Z)-enyl)-estradiol

[0109] 8β-(n-propyl)-estradiol

[0110] 8β-ethinyl-estradiol

[0111] 17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0112] 17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol

[0113] 16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol

[0114] 8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol

[0115] 8β-methyl-estra-1,3,5(10)-triene-3,17α-diol

[0116] 8β-vinyl-estradiol-diacetate

[0117] 8β-methyl-estradiol-diacetate

[0118] 8β-vinyl-estradiol-17-valerianate

[0119] 17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol

[0120] 8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol

[0121] 8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.

[0122] Other possible configurations of this invention will emerge fromthe subclaims.

[0123] In addition to the above use of the compounds of general formulaI′, the invention also relates to the compounds of general formula Iitself. These are the compounds of general formula I′ excluding thecompounds of general formula I′, in which

[0124] R³ is a hydroxy, methoxy or acetyl group, and simultaneously

[0125] R² represents a hydrogen atom,

[0126] R⁶, R^(6′), R⁷ and R^(7′) in each case represent a hydrogen atom;

[0127] R⁸ represents a methyl group,

[0128] R⁹ represents a hydrogen atom or

[0129] R⁹ and R¹¹ together represent an additional bond,

[0130] R^(11′) and R¹² in each case represent a hydrogen atom,

[0131] R¹⁴, R¹⁵, R^(15′), R¹⁶ and R^(16′) in each case represent ahydrogen atom, and

[0132] R¹⁷ and R^(17′) stands for a β-hydroxy group and a hydrogen atom;for a β-(2-bromoacetyl)oxy group and a hydrogen atom; for a β-acetylgroup and a hydrogen atom; a β-carboxyl group and a hydrogen atom; or

[0133] R¹⁷ and R^(17′) together represent an oxygen atom.

[0134] This group of compounds that is disclaimed from the scope ofgeneral formula I′ is already known from the following patent andbibliographic references:

[0135] FR M2743

[0136] Los, Marinus; U.S. Pat. No. 3,806,546

[0137] Los, Marinus; U.S. Pat. No. 3,736,345

[0138] Los, Marinus; U.S. Pat. No. 3,681,407

[0139] Los, Marinus; U.S. Pat. No. 3,501,530

[0140] Nagata, Wataru; Itazaki, Hiroshi; JP 45024573

[0141] Nagata, Wataru; Itazaki, Hiroshi; Takegawa, Bunichi; JP 45024139

[0142] Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004060

[0143] Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004059

[0144] Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004058

[0145] Sakai, Kiyoshi; Amemiya, Shigeo; Chem. Pharm. Bull. (1970),18(3), 641-3

[0146] Yoshioka, Kouichi; Goto, Giichi; Hiraga, Kentaro; Miki, Takuichi;Chem. Pharm. Bull. (1973), 21(11), 2427-31

[0147] Tori, K.; Editor(s): James, Vivian H. T.: Horm. Steroids, Proc.Int. Congr., 3rd (1971), Meeting Date 1970, 205-13

[0148] Tsukuda, Yoshisuke; Sato, Tomohiro; Shiro, Motoo; Koyama, Hirozo;J. Chem. Soc. B (1969), (4), 336-41

[0149] Tsukuda, Yoshiko; Itazaki, Hiroshi; Nagata, Wataru; Sato,Tomohiro; Shiro, Motoo; Koyama, Hirozo; Chem. Ind. (London) (1967),(48), 2047-8

[0150] Nakai, Hisayoshi; Koyama, Hirozo; Acta Crystallogr. (1967),23(4), 674.

[0151] A selective estrogenic action and the use of the known compoundsin terms of this invention have not yet been described, however.

[0152] In most cases, the already known estratrienes are described asintermediate compounds, as estrogens in the conventional sense or foruse in analytical processes.

[0153] In the compounds of general formulas I and I′ and in partialstructures II and II′ that are described below, a fluorine, chlorine,bromine or iodine atom can always stand for a halogen atom; a fluorineatom is preferred in each case. For the 11β-position, in particular alsoa chlorine atom can be named as a substituent. In particular, thehydrocarbon radicals, which can be partially or completely halogenated,are fluorinated radicals.

[0154] Hydrocarbon radical R¹⁸ is, for example, a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl,heptyl or hexyl radical.

[0155] Alkoxy groups OR¹⁸ in the compounds of general formulas I and I′and in partial structures II and II′ that are described below cancontain 1 to 6 carbon atoms in each case, whereby methoxy, ethoxy,propoxy, isopropoxy and t-butyloxy groups are preferred.

[0156] Representatives of the C₁-C₅-alkyl radicals R²⁰ and R²¹ aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl and neopentyl.

[0157] As representatives of straight-chain or branched-chainhydrocarbon radicals R²² with 1 to a maximum of 10 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl can be mentioned;methyl, ethyl, propyl and isopropyl are preferred.

[0158] As perfluorinated alkyl groups, for example, trifluoromethyl,pentafluorethyl and nonafluorobutyl can be mentioned. Representatives ofthe partially fluorinated alkyl groups are, for example,2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl,6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.

[0159] As a C₃-C₇-cycloalkyl group, a cyclopropyl, butyl, pentyl, hexylor heptyl group can be mentioned.

[0160] A C₄-C₁₅-cycloalkylalkyl radical has 3 to 7 carbon atoms in thecycloalkyl portion; typical representatives are the cycloalkyl groupsthat are mentioned directly above. The alkyl portion has up to 8 carbonatoms.

[0161] As examples of a C₄-C₁₅-cycloalkylalkyl radical, thecyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl,cyclopentylpropyl group, etc., can be mentioned.

[0162] In terms of this invention, an aryl radical is a phenyl, 1- or2-naphthyl radical; the phenyl radical is preferred.

[0163] Aryl always also includes a heteroaryl radical. Examples of aheteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, thepyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

[0164] As substituents for an aryl or heteroaryl radical, for example, amethyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-,trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-,mono(C₁₋₈-alkyl)- or di(C₁₋₈-alkyl)amino, whereby both alkyl groups areidentical or different, di(aralkyl)amino, whereby both aralkyl groupsare identical or different, can be mentioned.

[0165] An aralkyl radical is a radical that contains in the ring up to14, preferably 6 to 10, C atoms and in the alkyl chain 1 to 8,preferably 1 to 4, C atoms. Thus, as aralkyl radicals, for example,benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl,thienylethyl, and pyridylpropyl are suitable. The rings can besubstituted in one or more places by halogen, OH, O-alkyl, CO₂H,CO₂-alkyl, —NO₂, —N₃, —CN, C₁-C₂₀-alkyl, C₁-C₂₀-acyl, or C₁-C₂₀-acyloxygroups.

[0166] The alkyl groups or hydrocarbon radicals can be partially orcompletely fluorinated or substituted by 1-5 halogen atoms, hydroxygroups or C₁-C₄-alkoxy groups.

[0167] A vinyl or allyl radical is primarily defined with aC₂-C₅-alkenyl radical.

[0168] Other variants of the invention provide one or more, optionallyconjugated double bonds in rings B, C and D of the estratriene skeleton,specifically one or more double bonds in positions 6, 7; 7, 8; 9, 11;11, 12; 14, 15 and 15, 16. In this case, a double bond in position 7, 8or in position 11, 12 or two double bonds in positions 6, 7 and 8, 9 arepreferred (i.e., the naphthalene system is formed together with thearomatic A-ring).

[0169] One or more hydroxyl groups at C atoms 3, 16 and 17 can beesterified with an aliphatic, straight-chain or branched-chain,saturated or unsaturated C₁-C₁₄-mono- or polycarboxylic acid or anaromatic carboxylic acid or with an α- or β-amino acid.

[0170] Suitable as such carboxylic acids for esterification are, forexample:

[0171] Monocarboxylic acids: formic acid, acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalicacid, lauric acid, myristic acid, acrylic acid, propiolic acid,methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, andelaidic acid.

[0172] Esterification with acetic acid, valeric acid or pivalic acid ispreferred.

[0173] Dicarboxylic acids: oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid,sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid,and mesaconic acid.

[0174] Aromatic carboxylic acids: benzoic acid, phthalic acid,isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluicacid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, andisonicotinic acid.

[0175] Esterification with benzoic acid is preferred.

[0176] As amino acids, the representatives of these classes ofsubstances that are known sufficiently to one skilled in the art aresuitable, for example, alanine, β-alanine, arginine, cysteine, cystine,glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.

[0177] Esterification with β-alanine is preferred.

[0178] Preferred according to this invention are the compounds below:

[0179] 8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol

[0180] 3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol

[0181]8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol

[0182]8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol

[0183] 8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0184] 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol

[0185] 8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol

[0186] 8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol

[0187] 8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol

[0188] 8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol

[0189] 8β-vinyl-estradiol-3-sulfamate

[0190] 8β-vinyl-estradiol-3,17-disulfamate

[0191] 8β-vinyl-estradiol-3-(N-acetyl)-sulfamate

[0192] 8β-vinyl-estrone-3-sulfamate

[0193] 8β-vinyl-estron-3-acetate

[0194] 8β-vinyl-estriol

[0195] 8β-vinyl-estriol-3-sulfamate

[0196] 8β-methyl-estrone-3-sulfamate

[0197] 8β-methyl-estriol

[0198] 8β-(prop-(Z)-enyl)-estradiol

[0199] 8β-(n-propyl)-estradiol

[0200] 8β-ethinyl-estradiol

[0201] 17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0202] 17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol

[0203] 16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol

[0204] 8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol

[0205] 8β-methyl-estra-1,3,5(10)-triene-3,17α-diol

[0206] 8β-vinyl-estradiol-diacetate

[0207] 8β-methyl-estradiol-diacetate

[0208] 8β-vinyl-estradiol-17-valerianate

[0209] 17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol

[0210] 8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol

[0211] 8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.

[0212] Another aspect of this invention relates to the use of thestructural part of Formula II(8β-subst.-estra-1,3,5(10)triene-structural part)

[0213] in which R⁸ represents a straight-chain or branched-chain,optionally partially or completely halogenated alkyl or alkenyl radicalwith up to 5 carbon atoms, an ethinyl or prop-1-inyl radical, as acomponent of the total structure of compounds that have in vitrodissociation with respect to binding to estrogen receptor preparationsof rat prostates and rat uteri, and especially as a component of thetotal structure of such compounds that have a dissociation in favor oftheir estrogenic action on bone rather than the uterus.

[0214] In addition to the aromatic A-ring, one or more double bonds canbe present in the B-, C- and/or D-ring in positions 6(7); 9(11); 11(12);14(15) and 15(16).

[0215] The possible substituents at carbon atoms 6, 7, 11, 15 and 16 canbe respectively in α- or β-position.

[0216] This invention preferably relates to those structural parts ofgeneral formula II′

[0217] in which R⁸ represents a straight-chain or branched-chain,optionally partially or completely halogenated alkyl or alkenyl radicalwith up to 5 carbon atoms, an ethinyl or prop-1-inyl radical.

[0218] In the same manner, these structural parts can have one or moredouble bonds in the B-, C- and/or D-ring in addition to the aromaticA-ring.

[0219] The possible substituents at carbon atoms 6, 7, 11, 15, 16 and 17can in turn be in α- or β-position in each case.

[0220] As prodrugs, the esters of the 8β-substituted estratrienesaccording to the invention have advantages compared to the unesterifiedactive ingredients with respect to their method of administration, theirtype of action, strength and duration of action.

[0221] The sulfamates of 8β-substituted estratrienes according to theinvention also have pharmacokinetic and pharmacodynamic advantages.Related effects were already described in other steroid-sulfamates (J.Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest.Drugs 7, 575-589 (1998)).

[0222] In this patent application, steroids on which the 8β-substitutedestra-1,3,5(10)triene skeleton is based are described for the treatmentof estrogen receptor β-mediated diseases and conditions as selectiveestrogens, which have in vitro dissociation with respect to binding toestrogen receptor preparations of rat prostates and rat uteri and whichhave in vivo preferably a dissociation, for example, with respect tobone action rather than uterus action: these substances act in abone-protective manner over a wide dose range without stimulating theuterus.

[0223] In addition, the substances in the male rat can have protectiveaction against orchiectomy-induced bone mass loss, without inhibitingthe secretion of pituitary hormones LH and FSH. Their liver action issmall in the same dose range.

[0224] In addition, the substances exert an estrogen-like action on thevascular system and brain functions. Substances with higher binding tothe rat prostate—compared to the rat uterus estrogen receptor—are morepotent with respect to increasing the expression of serotonin receptorsand transporters, in comparison to their positive effect on the LHrelease. Processes in whose regulation of neurotransmitters serotonin isinvolved are therefore advantageously influenced, and the compoundsaccording to the invention exert an advantageous influence especially onmood and cognition.

[0225] They can be used as estrogens in the terms described in WO97/45125 for the production of medications for influencing the level ofserotonin or serotonin mRNA in humans.

[0226] It was found that the 8β-substituted estra-1,3,5(10)trienesaccording to the invention are suitable as selective estrogens for thetreatment of various conditions and diseases that are characterized by ahigher content of estrogen receptor β than estrogen receptor α in thecorresponding target tissue or target organ.

[0227] The invention also relates to pharmaceutical preparations thatcontain at least one compound of general formula I (or physiologicallycompatible addition salts with organic and inorganic acids thereof) andthe use of the compounds of general formula I′ for the production ofpharmaceutical agents, especially for the indications below.

[0228] The compounds can be used for the following indications afterboth oral and parenteral administration.

[0229] The novel selective estrogens that are described in this patentcan be used as individual components in pharmaceutical preparations orin combination especially with antiestrogens or gestagens. Especiallypreferred is the combination of selective estrogens with ERα-selectiveantiestrogens, or with antiestrogens that are peripherally-selectivelyactive, i.e., that do not pass through the blood-brain barriers.

[0230] The substances and the pharmaceutical agents that contain themare especially suitable for the treatment of peri- and postmenopausalsymptoms, especially hot flashes, sleep disturbances, irritability, moodswings, incontinence, vaginal atrophy, and hormone-deficiency-inducedemotional diseases. The substances for hormone substitution and thetherapy of hormone-deficiency-induced symptoms in the case of surgical,medicinal or ovarian dysfunction that is caused in some other way arealso suitable. Prevention of bone mass loss in postmenopausal women andmale-menopausal men, in women who have undergone hysterectomies or inwomen who were treated with LHRH agonists or LHRH antagonists is alsopart of this.

[0231] The compounds are also suitable for alleviating symptoms of malemenopause and female menopause, i.e., for male and female hormonereplacement therapy (HRT), specifically both for prevention and fortreatment, in addition for treatment of symptoms that are accompanied bya dysmenorrhea as well as for treatment of acne.

[0232] In addition, the substances can be used for prophylaxis againsthormone-deficiency-induced bone mass loss and osteoporosis, forprevention of cardiovascular diseases, especially vascular diseases suchas arteriosclerosis, for inhibition of the proliferation of arterialsmooth muscle cells, for treatment of primary pulmonary high bloodpressure and for prevention of hormone-deficiency-inducedneurodegenerative diseases, such as Alzheimer's disease, as well ashormone-deficiency-induced impairment of memory and learning capacity.

[0233] In addition, the substances can be used for treatment ofinflammatory diseases and diseases of the immune system, especiallyauto-immune diseases, such as, e.g., rheumatoid arthritis.

[0234] In addition, the compounds can be used for the treatment of malefertility disorders and prostatic diseases.

[0235] The compounds can also be used in combination with the naturalvitamin D3 or with calcitriol analogues for bone formation or assupporting therapies to therapies that cause bone mass loss (forexample, therapy with glucocorticoids, chemotherapy).

[0236] Finally, the compounds of general formula I′ can be used inconnection with progesterone receptor antagonists, specificallyespecially for use in hormone replacement therapy and for treatment ofgynecological disorders.

[0237] A therapeutic product that contains an estrogen and a pureantiestrogen for simultaneous, sequential or separate use for theselective estrogen therapy of perimenopausal or postmenopausalconditions is already described in EP-A 0 346 014.

[0238] The amount of a compound of general formula I′ that is to beadministered varies within a wide range and can cover any effectiveamount. On the basis of the condition that is to be treated and the typeof administration, the amount of the compound that is administered canbe 0.01 μg/kg-10 mg/kg of body weight, preferably 0.04 μg/kg-1 mg/kg ofbody weight, per day.

[0239] In humans, this corresponds to a dose of 0.8 μg to 800mg,preferably 3.2 μg to 80 mg, daily.

[0240] According to the invention, a dosage unit contains 1.6 μg to 200mg of one or more compounds of general formula I′.

[0241] The compounds according to the invention and the acid additionsalts are suitable for the production of pharmaceutical compositions andpreparations. The pharmaceutical compositions or pharmaceutical agentscontain as active ingredients one or more of the compounds according tothe invention or their acid addition salts, optionally mixed with otherpharmacologically or pharmaceutically active substances. The productionof the pharmaceutical agents is carried out in a known way, whereby theknown and commonly used pharmaceutical adjuvants as well as othercommonly used vehicles and diluents can be used.

[0242] As such vehicles and adjuvants, for example, those are suitablethat are recommended or indicated in the following bibliographicreferences as adjuvants for pharmaceutics, cosmetics and related fields:Ullmans Encyklopädie der technischen Chemie [Ullman's Encyclopedia ofTechnical Chemistry], Volume 4 (1953), pages 1 to 39; Journal ofPharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued byCzetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete[Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue,2,1961, p. 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fürPharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants forPharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf inWürttemberg 1971.

[0243] The compounds can be administered orally or parenterally, forexample intraperitoneally, intramuscularly, subcutaneously orpercutaneously. The compounds can also be implanted in the tissue.

[0244] For oral administration, capsules, pills, tablets, coatedtablets, etc., are suitable. In addition to the active ingredient, thedosage units can contain a pharmaceutically compatible vehicle, such as,for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid,talc, etc.

[0245] For parenteral administration, the active ingredients can bedissolved or suspended in a physiologically compatible diluent. Asdiluents, very often oils with or without the addition of a solubilizer,a surfactant, a suspending agent or an emulsifying agent are used.Examples of oils that are used are olive oil, peanut oil, cottonseedoil, soybean oil, castor oil and sesame oil.

[0246] The compounds can also be used in the form of a depot injectionor an implant preparation, which can be formulated so that a delayedrelease of active ingredient is made possible.

[0247] As inert materials, implants can contain, for example,biodegradable polymers, or synthetic silicones such as, for example,silicone rubber. In addition, for percutaneous administration, theactive ingredients can be added to, for example, a patch.

[0248] For the production of intravaginal systems (e.g., vaginal rings)or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena^((R)))that are loaded with active compounds of general formula I′ for localadministration, various polymers are suitable, such as, for example,silicone polymers, ethylene vinyl acetate, polyethylene orpolypropylene.

[0249] To achieve better bio-availability of the active ingredient, thecompounds can also be formulated as cyclodextrin clathrates. For thispurpose, the compounds are reacted with α-, β-, or γ-cyclodextrin orderivatives of the latter (PCT/EP95/02656).

[0250] According to the invention, the compounds of general formula I′can also be encapsulated with liposomes.

[0251] Methods

[0252] Estrogen Receptor Binding Studies

[0253] The binding affinity of the new selective estrogens was tested incompetitive experiments with use of 3H-estradiol as a ligand to estrogenreceptor preparations of rat prostates and rat uteri. The preparation ofprostate cytosol and the estrogen receptor test with prostate cytosolwas carried out as described by Testas et al. (1981) (Testas, J. et al.,1981, Endocrinology 109: 1287-1289).

[0254] The preparation of rat uterus cytosol as well as the receptortest with the ER-containing cytosol were basically performed asdescribed by Stack and Gorski, 1985 (Stack, Gorski 1985, Endocrinology117, 2024-2032) with some modifications as described in Fuhrmann et al.(1995) (Fuhrmann, U. et al. 1995, Contraception 51: 45-52).

[0255] The substances that are described in this patent have higherbinding affinity to the estrogen receptor of rat prostates than toestrogen receptors of rat uteri. In this case, it is assumed that ERβpredominates in the rat prostates over ERα, and ERα predominates in ratuteri over ERβ. Table 1 shows that the ratio of the binding to prostateand uterus receptors qualitatively coincides with the quotient ofrelative binding affinity (RBA) to human ERβ and ERα of rats (accordingto Kuiper et al. (1996), Endocrinology 138: 863-870) (Table 1). TABLE 1prost. Rat ER/ hERα hERβ ERβ/ uterus Rat prost. uterus EstrogenStructure RBA* RBA* ERα ER(RBA) ER(RBA) ER Estra- diol

100  100  1 100 100 1 Estrone

60 37 0.6 3 2 0.8 17α- Estra- diol

58 11 0.2 2.4 1.3 0.5 Estriol

14 21 1.5 4 20 5 5- Andro- stene- diol

 6 17 3 0.1 5 50 Geni- steine

 5 36 7 0.1 10 100 Coumes- trol

94 185  2 1.3 24 18

[0256] Table 2 shows the results for the compound8β-methyl-estra-1,3,5(10)-triene-3,17β-diol (compound D) that is to beused according to the invention as well as for the compounds accordingto the invention

[0257] 8β-Vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol (A)

[0258] 8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol (B)

[0259] 8β-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol (C) and

[0260] 8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol (E). TABLE 2 RBA RBACompound Rat Uterus Rat Prostate 8β-Vinyl-estra- 1 831,3,5(10),9(11)-tetraene- 3,17β-diol (A) 8β-Vinyl-estra-1,3,5(10)- 0.763 triene-3,17β-diol (B) 8β-(2,2-Difluorovinyl)-estra- 0.9 51,3,5(10)-triene-3,17β-diol (C) 8β-Methyl-estra-1,3,5(10)- 1.3 67triene-3,17β-diol (D) 8β-Ethyl-estra-1,3,5(10)- <0.3 7 triene-3,17β-diol(E)

[0261] Compounds A, B, C, D and E show a higher binding affinity to theestrogen receptor of rat prostates than to the estrogen receptor of ratuteri.

[0262] In addition, the predictability of the ‘prostate-ER versus theuterus-ER test system’ was confirmed with respect to tissue-selectiveaction by in vivo studies. Substances with a preference for prostate-ERare dissociated in vivo preferably with respect to bone and uterusaction in favor of action on bones. In addition, substances with higherbinding to the rat prostate—compared to the rat uterus estrogenreceptor—are more potent with respect to increasing the expression ofserotonin receptors and transporters, in comparison to their positiveeffect on the LH release.

[0263] Bone Studies

[0264] Three-month-old female rats are ovariectomized and treated oncedaily for 28 days with the test compound immediately after theoperation. The administration is carried out subcutaneously in arachisoil/ethanol. The animals are sacrificed on the day after the lastadministration, and tibia as well as uteri are removed. The uteri areweighed, fixed and worked up for histological studies. The determinationof bone density is carried out ex vivo on prepared long bones by meansof pQCT (quantitative computer tomography). The measurements are made ata distance of 4-6 mm from the ball of the joint of the proximal tibia.

[0265] The ovariectomy reduces the density of the trabecular bone in themeasured area by about 400 mg of Ca²⁺/cm³ to about 300 mg of Ca²⁺/cm³.By treatment with a compound of general formula I according to thisinvention, the degradation of the bone density is prevented orinhibited. The bone density in the proximal tibia was measured.

[0266] The higher binding affinity to the estrogen receptor of ratprostates than to the estrogen receptor of rat uteri is reflected invivo preferably in considerably lower amounts of the compounds accordingto the invention, which produce a 50% bone protection, in comparison tothe amounts that produce a 50% uterus stimulation, relative to the bonemass loss, which can be measured in ovariectomized, untreated femalerats 28 days after the ovariectomy unlike in intact animals that aresubjected to sham operations.

[0267] The vascular action of the estrogens according to the inventionis determined in the model of the ApoE-knockout mouse, as described byR. Elhage et al., 1997, as well as in the model of theballoon-catheter-induced vascular damage (restenosis model) (Elhage, R.et al. 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17:2679-2684).

[0268] To detect the action of estrogens on the brain function, theoxytocin-, oxytocin receptor- or vasopressin-mRNA expression is used asa surrogate parameter (Hrabovszky, E. et al. 1998, Endocrinology 1339:2600-2604). Ovariectomized rats are treated for 7 days with the testsubstance or vehicle (administration: subcutaneous or oral, six timesdaily). On day 7 after the first administration, the animals aredecapitated, the uterus weight is determined, and the oxytocin-,oxytocin receptor-, or vasopressin-mRNA level is studied by means of insitu hybridization in suitable brain sections. The ED₅₀ values aredetermined with respect to stimulation of uterus growth and induction ofthe oxytocin receptor mRNA.

[0269] Another possibility to demonstrate in vivo the dissociatedestrogen action of the substances according to the invention consists inthe fact that after a one-time administration of the substances in rats,effects on the expression of 5HT2a-receptor and serotonin transporterprotein and mRNA levels in ERβ-rich brain areas can be measured.Compared to the effect on the serotonin receptor and transporterexpression, the effect on the LH-secretion is measured. Substances withhigher binding to the rat prostate—compared to the rat uterus estrogenreceptor—are more potent with respect to increasing the expression ofserotonin receptors and transporters, in comparison to their positiveeffect on the LH release. The density of serotonin receptors andtransporters is determined in brain sections using radioactive ligands,and the corresponding mRNA is determined using in situ hybridization.The method is described in the literature: G. Fink & B. E. H. Sumner1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular BrainResearch, in press.

[0270] In accordance with their stronger binding to the rat prostaterather than the rat uterus estrogen receptor, substances A, B, C, D andE according to the invention result in an increased expression of theserotonin receptor and transporter.

[0271] Production of the Compounds According to the Invention

[0272] The compounds of general formula I (or I′) according to theinvention are produced as described in the examples. Additionalcompounds of general formula I′ can be obtained by an analogousprocedure using reagents that are homologous to the reagents that aredescribed in the examples.

[0273] Etherification and/or esterification of free hydroxy groups iscarried out according to methods that are common to one skilled in theart.

[0274] The compounds according to the invention can be present in carbonatoms 6, 7, 11, 15, 16 and 17 as α,β-stereoisomers. In the production ofcompounds according to the described processes, the compounds in mostcases accumulate as mixtures of the corresponding α,β-isomers. Themixtures can be separated by, for example, chromatographic processes.

[0275] According to general formula I, possible substituents can alreadybe present in final form or in the form of a precursor even in thestarting product, a substituted estrone already corresponding to thedesired end product.

[0276] The introduction of a substituent or reactive precursor on carbonatom 7 by nucleophilic addition of the substituent or precursor on a6-vinylsulfone thus is possible (DE 42 18 743 A1). In this case, 7α- and7β-substituted compounds, which can be separated by, for example,chromatographic processes, are obtained in different proportions, basedon the reactants and the selected reaction conditions.

[0277] 17-Substituents are also introduced according to known processesby nucleophilic addition of the desired substituent or a reactiveprecursor thereof and are optionally further built up.

[0278] The 8β-substituted estratriene-carboxylic acid esters accordingto the invention are produced from the corresponding hydroxy steroidsanalogously to processes that are also known (see, e.g., PharmazeutischeWirkstoffe, Synthesen, Patente, Anwendungen [Pharmaceutical ActiveIngredients, Syntheses, Patents, Applications]; A. Kleemann, J. Engel',Georg Thieme Verlag Stuttgart 1978, Arzneimittel, Fortschritte[Pharmaceutical Agents, Improvements] 1972 to 1985; A. Kleemann, E.Lindner, J. Engel (Editors), VCH 1987, pp. 773-814).

[0279] The estratriene-sulfamates according to the invention areavailable in a way that is known in the art from the correspondinghydroxy steroids by esterification with sulfamoyl chlorides in thepresence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717(1996)).

[0280] Subsequent acylation of the sulfamide group results in the(N-acyl)sulfamates according to the invention, for which pharmacokineticadvantages were already detected in the case of the absence of an8-substituent (cf. DE 195 40 233 A1).

[0281] The regioselective esterification of polyhydroxylated steroidswith N-substituted and N-unsubstituted sulfamoyl chlorides is carriedout according to partial protection of those hydroxyl groups that are toremain unesterified. Silyl ethers have turned out to be protectivegroups with selective reactivity that is suitable for this purpose,since these silyl ethers are stable under the conditions of sulfamateformation, and the sulfamate group remains intact when the silyl ethersare cleaved again for regeneration of the residual hydroxyl group(s)still contained in the molecule (Steroids 61, 710-717 (1996)). Theproduction of the sulfamates according to the invention with one or moreadditional hydroxyl groups in the molecule is also possible in that thestarting material is suitable hydroxy-steroid ketones. First, dependingon the goal, one or more hydroxyl groups that are present are subjectedto sulfamoylation. Then, the sulfamate groups optionally can beconverted with a desired acyl chloride in the presence of a base intothe (N-acyl)sulfamates in question. The now present oxosulfamates oroxo-(N-acyl)sulfamates are converted by reduction into the correspondinghydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717(1996)). Sodium borohydride and the borane-dimethyl sulfide complex aresuitable as suitable reducing agents.

[0282] Functionalizations at carbon atom 2 are possible, for example, byelectrophilic substitution after prior deprotonation of the 2-positionof the corresponding 3-(2-tetrahydropyranyl)- or 3-methyl ether with alithium base (e.g., methyllithium, butyllithium). Thus, for example, afluorine atom can be introduced by reaction of the C—H-activatedsubstrate with a fluorinating reagent such as N-fluoromethanesulfonimide (WO 94/24098).

[0283] The introduction of variable substituents in rings B, C and D ofthe estratriene skeleton can basically be carried out according to thechemical teaching that is known to one skilled in the art, with whichthe corresponding estratriene derivatives that are not substituted in8-position are produced (see, i.a.: Steroide [Steroids], L. F. Fieser,M. Fieser, Verlag Chemie, Weinheim/Bergstr., 1961; Organic Reactions inSteroid Chemistry, J. Fried, J. A. Edwards, Van Nostrand ReinholdCompany, New York, Cincinnati, Toronto, London, Melbourne, 1972;Medicinal Chemistry of Steroids, F. J. Zeelen, Elsevier, Amsterdam,Oxford, New York, Tokyo, 1990). This relates to, for example, theintroduction of substituents, such as hydroxyl or alkyloxy groups,alkyl, alkenyl or alkinyl groups or halogen, especially fluorine.

[0284] Substituents according to general formula I can also beintroduced in the stage of estratrienes that are already substituted in8-position, however. This can be useful or necessary especially in thecase of multiple substitutions of the desired final compound.

[0285] The examples below are used for a more detailed explanation ofthe invention.

[0286] The general synthesis routes for these examples are shown indiagrams 1 to 3.

[0287] As starting material for such syntheses, 11-keto-estratetraenederivatives of type 1 or 2 (U.S. Pat. No. 3,491,089, TetrahedronLetters, 1967, 37, 3603), which are substituted stereoselectively in8β-position in the reaction with diethylaluminum cyanide, are used. Bysubsequent reduction of the carbonyl function at C(11) and eliminationof the hydroxyl group that is produced, 8β-substitutedestra-1,3,5(10),9(11)-tetraenes, which in turn can be converted into8β-aldehydes, are obtained. A functionalization, e.g., by Wittigreactions with subsequent removal of protective groups, results in the8β-steroids according to the invention.

[0288] The 11-oxidized estradiol derivatives that are first obtained inthis sequence can be further reacted to many substitution patterns onthe steroid like the double bond C(9)-C(11) according to methods thatare known to one skilled in the art. For example, an 11α-hydroxy groupcan be converted into an 11β-fluorine atom according to the process thatis described by Vorbrüggen et al.

[0289] For the production of the derivatives of 8β-substitutedestra-1,3,5(10)-triene-3,16ξ-diols according to the invention without17-substituents, mainly the following synthesis strategy is used. Inthis connection, the 8β-carbonyl function is protected as an acetal.After subsequent oxidation, the 17-ketosteroid can be converted into asulfonylhydrazone, in the simplest case by reaction with phenylsulfonylhydrazide. By a degradation reaction, the formation of the C(16)-C(17)olefin is carried out (Z. Chem. 1970, 10, 221-2; Liebigs Ann. Chem.1981, 1973-81), on which hypobromide is stored in aregio/stereocontrolled way. Reductive dehalogenation and removal of theacetal protective group at 8β opens the way for transformations to thecompounds according to the invention. The 16β-alcohols that can beobtained according to this method can be converted into the 16α-epimerby known methods (Synthesis 1980, 1).

[0290] Another variant for the introduction of the hydroxyl group atC-atom 16 consists in the hydroboration of the 16(17)-double bond withsterically exacting boranes. Of this reaction, it is known that itresults in 16-oxidized products (Indian J. Chem. 1971, 9, 287-8). Thereaction of the estra-1,3,5(10),16-tetraene 17 with9-borabicyclo[3.3.1]nonane after the oxidation with alkaline hydrogenperoxide consequently produces 16α-hydroxyestratrienes. The epimeric16β-hydroxy steroids are formed to a lesser extent in this reaction.Further transformations on the 8β-substituent then result in thecompounds of general formula I according to the invention.

[0291] Characteristic, but not limiting synthesis processes, which areuseful for providing representative substitution patterns on the estroneskeleton, also in combination with several substituents, are found in,for example: C(1) J. Chem. Soc. (C) 1968, 2915; C(7) Steroids 54, 1989,71; C(8α) Tetrahedron Letters 1991, 743; C(8β) Tetrahedron Letters 1964,1763; J. Org. Chem. 1970, 35, 468; C(11) J. Steroid Biochem. 31, 1988,549; Tetrahedron 33, 1977, 609 and J. Org. Chem. 60, 1995, 5316; C(9)DE-OS 2035879; J. Chem. Soc. Perk. 1 1973, 2095; C(15) J. Chem. Soc.Perk. 1 1996, 1269.); C(13α) Mendeleev Commun. 1994, 187; C(14β) Z.Chem. 23, 1983, 410.

[0292] In the examples and in the diagrams, the following abbreviationsapply:

[0293] THF=tetrahydrofuran; THP=tetrahydropyran-2-yl; DHP=dihydropyran;DMSO=dimethyl sulfoxide; MTBE=methyl-tert-butyl ether;DIBAH=diisobutyl-aluminum hydride;LTBAH=lithium-tri-tert.-butoxyaluminum hydride.

EXAMPLE 1

[0294]3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),8-tetraen-11-one(2)

[0295] 47 ml of dihydropyran and 0.96 g of pyridine toluenesufonate wereadded at room temperature to 15.29 g of11-keto-3-methoxy-estra-1,3,5(10),8-tetraen-17β-ol (1) in 35 ml ofdichloromethane, and it was stirred for 2 hours. Then, the reactionsolution was shaken several times with saturated sodium bicarbonatesolution, washed with water and dried with magnesium sulfate. Thesolvent was evaporated in a vacuum, and the residue was purified onsilica gel (solvent mixture: cyclohexane/ethyl acetate=8/2). 16.8 g(83%) of light yellowish, viscous oil was thus obtained.

[0296]8β-cyano-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-11-one(3)

[0297] 195 ml of diethylaluminum cyanide (1.0 M, in toluene) was addedin drops at a temperature of −5° C. under argon to a solution of 24.5 gof 11-ketosteroid 2 in 330 ml of toluene, and it was stirred for 1.5hours while cooling was continued. Then, the mixture was poured onto 470ml of ice-cooled 1N sodium hydroxide solution, stirred for 1 hour,extracted several times with ethyl acetate, and the collected organicphases were washed with water and brine and dried with magnesiumsulfate. The chromatography of the evaporation residue on silica gel(solvent mixture: cyclohexane/ethyl acetate=4/1) yielded 3 as a foam ina yield of a total of 12.0 g (37%).

[0298]8β-cyano-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-11-ol(4)

[0299] A solution of 33.1 g of steroid 3 in 400 ml of THF was cooled to0° C., mixed in portions with 51.0 g of LTBAH, and the solution wasstirred for 1 hour while cooling was continued and for 1 hour at roomtemperature. 25 ml of saturated sodium bicarbonate solution was added indrops to the reaction solution at 0° C., the precipitate that wasproduced was separated by filtration on Celite, and the filtrate wasconcentrated by evaporation to a very large extent. The residue wasextracted several times with ethyl acetate, the collected organic phaseswere then washed with brine, dried on magnesium sulfate, and the solventwas removed in a vacuum. In this way, 27.6 g (97%) of foamy 4 wasobtained, which was used without further purification in the next stage.

[0300]8-cyano-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraene(5)

[0301] 27.6 ml of phosphorus oxychloride was added in drops to asolution of 27.6 g of 4 in 275 ml of pyridine at a temperature of 0-5°C., and it was stirred for another 1.5 hours at this temperature. Then,the mixture was moved into a dropping funnel and added in drops to anice-cooled, saturated sodium bicarbonate solution. Then, it wasextracted with dichloromethane, the collected organic phases were washedwith brine, dried on magnesium sulfate, and the solvent was removed in avacuum. In this way, 23.5 g (89%) of almost colorless, foamy 5 wasobtained, which was used without further purification in the next stage.

[0302] 8β-carbonyl-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol (6)

[0303] A solution of 41 ml of DIBAH in 100 ml of toluene was added indrops to 11.4 g of 8β-cyano-steroid 5 in 70 ml of toluene under argon at0° C., and it was stirred for 1.5 hours at this temperature. Thesolution was mixed at 0° C. in succession with 33 ml of ethanol, 33 mlof ethanol-water mixture (v/v=1/1) and 120 ml of semi-concentratedhydrochloric acid, and then refluxed for 2 hours. The mixture wasextracted several times with ethyl acetate, the collected organic phaseswere washed with water, dried with magnesium sulfate and evaporated tothe dry state in a vacuum. By chromatography of the residue on silicagel (solvent mixture: cyclohexane/ethyl acetate=3/2), 3.21 g (35%) offoamy 6 was obtained.

[0304] 3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol (7a)

[0305] 0.18 ml of hydrazinium hydroxide (80%, with water) and 50 mg of8β-carbonyl-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol (6) in 6.5 mlof triethylene glycol were added to a solution of 225 mg of potassiumhydroxide in 3.5 ml of triethylene glycol at room temperature and heatedfor 2 hours to 200° C. After cooling, it was mixed in succession with 10ml of water and 3 ml of 10% sulfuric acid. The mixture was extractedseveral times with ether, the collected organic phases were washed withwater, dried with magnesium sulfate and evaporated to the dry state in arotary evaporator. The chromatography of the residue on silica gel(solvent mixture: cyclohexane/ethyl acetate=8/2) yielded 36 mg (79%) of3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol with a meltingpoint of 168° C.

EXAMPLE 2

[0306] The synthesis of substance 7a was described under Example 1,1.1-1.6.

[0307] 3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol (8a)

[0308] 75 mg of 3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol(7a) was dissolved in a solvent mixture that consists of 3.5 ml of THFand 1.5 ml of methanol and stirred with 75 mg of palladium (10%, onmagnesium carbonate) for 3.75 hours at room temperature under hydrogenatmosphere. Then, the reaction solution was filtered on Celite, thefiltrate was evaporated to the dry state in a rotary evaporator, and thethus obtained TLC-uniform, foamy product (74 mg, 98%) was used withoutfurther purification in the next stage.

[0309] 8β-methyl-estra-1,3,5(10)-triene-3,17β-diol (8b)

[0310] 74 mg of 3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol wasdissolved in 3 ml of anhydrous toluene, cooled to 0° C. and mixedcarefully under argon with 0.6 ml of DIBAH. The reaction mixture wasslowly refluxed, and it was kept at this temperature for 3.5 hours.Then, it was cooled again to 0° C., the solution was mixed in successionwith 2 ml of ethanol, 2 ml of ethanol-water mixture (v/v=1/1) and 2 mlof semi-concentrated hydrochloric acid and extracted several times withethyl acetate. The collected organic phases were washed neutral withwater, dried with magnesium sulfate and evaporated to the dry state in avacuum. 70 mg (99%) of colorless crystals with a melting point of168-170° C. was obtained.

EXAMPLE 3

[0311] The synthesis of substance 6 was described under Example 1, 1.1-1.5.

[0312]8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraene(9)

[0313] A solution of 500 mg of 6 in 10 ml of dichloromethane was mixedwith 1.45 ml of 3,4-dihydro-2H-pyran and 28 mg (0.11 mmol) of pyridinetoluenesulfonate and stirred for 16 hours at room temperature. Themixture was washed in succession several times with saturated sodiumbicarbonate solution and water, and the organic phase was evaporated tothe dry state in a vacuum after drying with magnesium sulfate. Product 9accumulated as a foam in a yield of 527 mg (86%).

[0314]3-methoxy-17β-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10),9(11)-tetraene(10a)

[0315] A solution of 585 mg of8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraenein 25 ml of DMSO was mixed under argon first with 4.92 g ofmethyltriphenylphosphonium bromide, then carefully with 394 mg of sodiumhydride (80%, in paraffin oil), and then heated for 2 hours slowly to aninternal temperature of 55° C. After cooling, 25 ml of water was addedin drops, extracted several times with diethyl ether, washed with water,and the collected organic phases were dried with magnesium sulfate.After the solvent was removed, the residue was purified bychromatography on silica gel (solvent mixture: cyclohexane/MTBE=30/1).520 mg (89%) of 8β-vinyl steroid in the form of a colorless foam wasobtained.

[0316] 8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol (11a)

[0317] 550 mg of3-methoxy-17β-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10),9(11)-tetraenewas reacted according to general operating instructions 19. The yield ofcolorless crystals with a melting point of 149-150° C. was 315 mg (76%).

[0318]8β-(2,2-difluorovinyl)-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraene(10b)

[0319] A solution of 0.22 ml of diethyl(difluoromethyl)phosphonate in0.4 ml of n-pentane and 2 ml of 1,2-dimethoxyethane were cooled underargon to −78° C., mixed with 0.82 ml of tert-butyllithium solution (1.7M, in n-pentane) and stirred for 0.25 hour at this temperature. At thesame temperature, a solution of 220 mg of8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraenein 3.5 ml of 1,2-dimethoxyethane and 0.58 ml of n-pentane were now addedin drops and stirred for 0.5 hour with continued cooling. Then, it washeated first to room temperature and then heated for 1 hour to aninternal temperature of 84° C. while the n-pentane was distilled off.After cooling, the batch was poured onto 20 ml of ice water, light brownprecipitate was filtered off, it was extracted with dichloromethane, andthe collected organic phases were dried with magnesium sulfate. Afterthe solvent was removed, the residue was purified by chromatography onsilica gel (solvent mixture: cyclohexane/MTBE=30/1). The yield of oily,almost colorless steroid was 108 mg (46%).

[0320] 8β-(2,2-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol(11b)

[0321] 105 mg of8β-(2,2-difluorovinyl)-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraenewas reacted according to general operating instructions 19 for ethercleavage with DIBAH/acid. The yield of colorless crystals with a meltingpoint of 103-106° C. was 75 mg (93%).

EXAMPLE 4

[0322] The synthesis of substance 9 was described under Example 3, 3.1.

[0323]8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene(12)

[0324] 1.73 g of 9 was dissolved in 75 ml of solvent mixture thatconsists of THF and methanol (v/v=7/3) and stirred with 1.0 g ofpalladium (10%, on magnesium carbonate) for 3.75 hours at roomtemperature under hydrogen atmosphere. Then, the reaction solution wasfiltered on Celite, the filtrate was evaporated to the dry state in arotary evaporator, and the thus obtained TLC-uniform, bright oil wasused without additional purification for other reactions.

[0325]3-methoxy-17β-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene(13a)

[0326] A solution of 2.47 g of8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraenein 100 ml of DMSO was mixed under argon first with 19.80 g ofmethyltriphenylphosphonium bromide, then carefully with 1.58 g of sodiumhydride (80%, in paraffin oil), and then heated slowly for 2 hours to aninternal temperature of 55° C. After cooling, 100 ml of water was addedin drops, extracted several times with diethyl ether, washed with water,and the collected, organic phases were dried with magnesium sulfate.After the solvent was removed, the residue was purified bychromatography on silica gel (solvent mixture: cyclohexane/MTBE=30/1).1.91 g (78%) of 8β-vinyl steroid was obtained as a colorless foam.

[0327] 8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol (14a)

[0328] 1.86 g of3-methoxy-17β-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-trienewas reacted according to general operating instructions 19. The crude8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol was obtained afterpurification on silica gel (solvent mixture: cyclohexane/ethylacetate=7/3) in the form of colorless crystals with a melting point of163-165° C. in a yield of 1.20 g (86%).

[0329]8β-(2,2-difluorovinyl)-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene(13b)

[0330] A solution of 0.6 ml of diethyl(difluoromethyl)phosphonate in 1.0ml of n-pentane and 5.6 ml of 1,2-dimethoxyethane were cooled underargon to −78° C., mixed with 2.2 ml of tert-butyllithium solution (1.7M, in n-pentane) and stirred for 0.25 hour at this temperature. At thesame temperature, a solution of 600 mg of8β-carbonyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraenein 9.2 ml of 1,2-dimethoxyethane and 1.6 ml of n-pentane were now addedin drops and stirred for 0.5 hour with continued cooling. Then, it washeated first to room temperature and then heated for 1 hour to aninternal temperature of 84° C. while the n-pentane was distilled off.After cooling, the batch was poured onto 40 ml of ice water, light brownprecipitate was filtered off, it was extracted with dichloromethane, andthe collected organic phases were dried with magnesium sulfate. Afterthe solvent was removed, the residue was purified by chromatography onsilica gel (solvent mixture: cyclohexane/MTBE=30/1). The yield of oily,almost colorless steroid was 75 mg (12%).

[0331] 8β-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol (14b)

[0332] According to general operating instructions 19., 78 mg of3-methoxy-8β-(2,2-difluorovinyl)-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienewas reacted. The yield of colorless crystals with a melting point of154-156° C. was 56 mg (90%).

EXAMPLE 5

[0333] The synthesis of substance 13a was described under Examples 4,4.2.

[0334]8β-ethyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene

[0335] 0.50 g of 13a was dissolved in 25 ml of solvent mixture thatconsists of THF and methanol (v/v=7/3) and stirred with 0.30 g ofpalladium (10% on magnesium carbonate) for 3.75 hours at roomtemperature under hydrogen atmosphere. Then, the reaction solution wasfiltered on Celite, the filtrate was evaporated to the dry state in arotary evaporator and the bright foam that was obtained was used withoutadditional purification in the next stage.

[0336] 8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol (15a, 15b)

[0337] 330 mg of crude8β-ethyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienefrom the last stage was reacted according to general operatinginstructions 6.1 and 6.2. By, chromatography on silica gel, epimericestratriene diols 15a and 15b in yields of 161 mg or 20 mg can beisolated from the accumulating crude product. The melting point for 15ais approximately 149-152° C. and that of 15b is approximately 185-187°C.

EXAMPLE 6

[0338] 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one

[0339] A solution of 700 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol in 30 ml ofdichloromethane was mixed with 740 mg of pyridinium chlorochromate andstirred for 3 hours at room temperature. By filtration of the reactionmixture on silica gel (solvent mixture: cyclohexane/ethyl acetate=7/3)and subsequent concentration by evaporation of the filtrate in a rotaryevaporator, 680 mg (98%) of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one was obtained as almostcolorless foam, which was used in the next stage without furtherpurification.

[0340] 3-hydroxy-8β-vinyl-estra-1,3,5(10)-trien-17-one

[0341] 460 mg of 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one wasadded to 9.2 g of pyridinium hydrochloride at 180° C. and stirred for 3hours at the same temperature. Then, it was poured onto ice, thedeposited precipitate was filtered off, washed with water and dried. Theyield of 2-hydroxy-8β-vinyl-estra-1,3,5(10)-trien-17-one with a meltingpoint of 239-242° C. amounted to 400 mg (90%).

EXAMPLE 7

[0342] 3-sulfamoyloxy-8β-vinyl-estra-1,3,5(10)-trien-17-one

[0343] 76 mg of 3-hydroxy-8β-vinyl-estra-1,3,5(10)-trien-17-one wasdissolved in 7 ml of dichloromethane, mixed with 0.26 ml of2,6-di-tert-butylpyridine and 221 mg of sulfamoyl chloride and stirredfor 1.5 hours at room temperature. Then, the reaction mixture was addedto water and extracted several times with dichloromethane. The collectedorganic phases were washed with saturated sodium chloride solution,dried on magnesium sulfate and concentrated by evaporation in a vacuumto the greatest extent possible. By chromatography of the residue thatis obtained on silica gel (solvent mixture: cyclohexane/ethylacetate=7/3), 46 mg (48%) of17-oxo-8β-vinyl-estra-1,3,5(10)-trien-3-yl-amidosulfonate was obtained.

[0344] 3-sulfamoyloxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol

[0345] 46 mg of17-oxo-8β-vinyl-estra-1,3,5(10)-trien-3-yl-amidosulfonate was dissolvedin 1.5 ml of THF and 1.5 ml of methanol, mixed at 0° C. with 33 mg ofsodium borohydride and stirred for 1 hour at 0° C. Then, 0.2 ml ofconcentrated acetic acid was added, and it was concentrated byevaporation in a vacuum. The residue was taken up in ethyl acetate andwater, the organic phase was separated, and the aqueous was extractedseveral times with ethyl acetate. The collected organic phases werewashed with saturated sodium chloride solution, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The crude productwas purified by chromatography on silica gel (solvent mixture:cyclohexane/ethyl acetate=6/4) and yielded 45 mg (98%) of17β-hydroxy-8β-vinyl-estra-1,3,5(10)-trien-3-yl-amidosulfonate in theform of fine small needles with a melting point of 82-86° C.

EXAMPLE 8

[0346]3-Methoxy-8β-prop-1-(Z)-enyl-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene

[0347] A solution of 100 mg of8β-formyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienein 5 ml of DMSO was mixed under argon first with 830 mg ofethyltriphenyl phosphonium bromide, then carefully with 64 mg of sodiumhydride (80% in paraffin oil) and then heated slowly for 2 hours to aninternal temperature of 60° C. After cooling, 10 ml of water was addedin drops, extracted several times with ethyl acetate, the collectedorganic phases were washed with water and dried on magnesium sulfate.After the solvent was removed, the residue was purified bychromatography on silica gel (solvent mixture: cyclohexane/ethylacetate=30/1). 24 mg (23%) of 8β-propenyl steroid in the form of acolorless foam was obtained.

[0348] 8β-prop-1-(Z)-enyl-estra-1,3,5(10)-triene-3,17β-diol

[0349] 24 mg of3-methoxy-8β-(prop-1-(Z)-enyl)-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienewas reacted according to the general operating instructions for cleavingTHP and 3-methyl ether. The crude8β-prop-1-(Z)-enyl-estra-1,3,5(10)-triene-3,17β-diol was obtained aftera purification on silica gel (solvent mixture: cyclohexane/ethylacetate=7/3) in the form of colorless crystals with a melting point of119-125° C. in a yield of 10 mg (66%).

EXAMPLE 9

[0350] 3-methoxy-17α-ethinyl-8β-vinyl-estra-1,3,5(10)-trien-17β-ol

[0351] Under argon, 85 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one in 8 ml of THF wasdissolved, cooled to −78° C. and mixed with 5.5 ml of ethinylmagnesiumbromide solution (0.5 M in THF) and 100 mg of lithium acetylide-ethylenediamine complex. While being heated to room temperature, the reactionmixture was stirred for 3 hours, then cooled to 0° C. and mixed with 10ml of saturated ammonium chloride solution. The mixture was extractedseveral times with ethyl acetate, the collected organic phases werewashed with saturated sodium chloride solution, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. By chromatographyof the residue on silica gel (solvent mixture: cyclohexane/ethylacetate=9:1), 30 mg (33%) of oily17α-ethinyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol wasobtained.

[0352] 17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0353] A solution of 15 mg of17α-ethinyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol and 82 mg oftetrabutylammonium iodide in 2 ml of dichloromethane was cooled underargon to −78° C., mixed with 0.3 ml of a boron trichloride solution (1 Min dichloromethane) and stirred for 24 hours at 0° C. Then, the reactionsolution was added in drops to a saturated ammonium chloride solutionthat was cooled to 5° C., the mixture was extracted several times withdiethyl ether, the collected organic phases were washed with saturatedsodium chloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. By chromatography of the residue on silica gel(solvent mixture: cyclohexane/ethyl acetate=7:3), 5 mg (35%) of17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol was obtained witha melting point of 156° C.

EXAMPLE 10

[0354] 3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5(10)-triene-17β-diol

[0355] A solution of 50 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one in 2 ml of anhydrous THFwas added in drops under argon to a solution of 1 ml of methyllithiumsolution (1.6 M in diethyl ether) that was cooled to −78° C., then 0.5ml of anhydrous dimethylformamide was added and stirred for 1.5 hourswhile being heated to room temperature. The mixture was mixed withsaturated sodium bicarbonate solution, extracted several times withethyl acetate, the collected organic phases were washed with water anddried on magnesium sulfate. By concentration by evaporation of theorganic phases, 42 mg (80%) of crude3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5(10)-trien-17β-ol was obtained,which was used for cleaving 3-methyl ether without further purification.

[0356] 17α-methyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0357] 40 mg of3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5(10)-trien-17β-ol was reactedaccording to the general operating instructions for cleaving 3-methylether. The thus obtained17α-methyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol was obtained in ayield of 30 mg (78%) with a melting point of 129-130° C. after apurification on silica gel (solvent mixture: cyclohexane/ethylacetate=7/3).

EXAMPLE 11

[0358] 3-methoxy-8β-vinyl-estra-1,3,5(10)-triene-17α-(4′-nitro)-benzoate

[0359] 0.48 ml of a 40% solution of diethylazodicarboxylate in toluenewas added in drops to a mixture that consists of 100 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol, 277 mg oftriphenylphosphine, 175 mg of 4-nitrobenzoic acid and 5 ml of toluene,and it was stirred for 3 hours at 60° C. After cooling, it was extractedseveral times with ethyl acetate, the collected organic phases werewashed in succession with saturated sodium bicarbonate solution andsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. By chromatography on silica gel(solvent mixture: n-hexane/ethyl acetate=25/1), 84 mg (57%) ofyellowish, oily3-methoxy-8β-vinyl-estra-1,3,5(10)-triene-17α-(4′-nitro)-benzoate wasobtained.

[0360] 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17α-ol

[0361] A solution of 80 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-triene-17α-(4′-nitro)-benzoate in 12ml of methanol and 0.4 ml of water was mixed with 480 mg of potassiumcarbonate and stirred for 24 hours at room temperature. Then, it wasconcentrated by evaporation in a vacuum to the greatest extent possible,the residue was taken up in water and extracted several times with ethylacetate. The collected organic phases were washed with saturated sodiumchloride solution, dried on magnesium sulfate and concentrated byevaporation in a rotary evaporator. In this way, 40 mg (54%) of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17α-ol was obtained.

[0362] 8β-vinyl-estra-1,3,5(10)-trien-3,17α-ol

[0363] 40 mg (0.13 mmol) of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17α-ol was reacted according tothe general operating instructions for cleaving 3-methyl ether. The8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol that was obtained in thiscase was obtained in a yield of 9 mg (24%) with a melting point of149-151° C. after a purification on silica gel (solvent mixture:cyclohexane/ethyl acetate=7/3).

EXAMPLE 12

[0364] 16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one

[0365] A solution of 150 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol in 6 ml of anhydrous THFthat was cooled to −40° C. was mixed under argon with 1.2 ml of asolution of lithium diisopropylamide (2 M in THF/n-heptane/ethylbenzene)and stirred for 1 hour at this temperature. Then, 0.24 ml of methyliodide was added at the same temperature and stirred for another hourwhile being heated to room temperature. Then, it was cooled to −5° C., 4ml of 2N sodium hydroxide solution was added, and the mixture wasextracted several times with ethyl acetate. The collected organic phaseswere washed with water, dried on MgSO₄ and concentrated by evaporationin a vacuum.

[0366] The crude product that was thus obtained was used again under thesame reaction conditions.

[0367] 130 mg (80%) of yellow-brown, oily16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one was obtainedas raw material.

[0368] 16-dimethyl-8β-vinyl-estra-1,3,5(10)-trien-3,17β-ol

[0369] 130 mg of crude16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one was reactedaccording to the general operating instructions for cleaving 3-methylether. The crude product that was obtained was purified bychromatography on silica gel (solvent mixture: cyclohexane/ethylacetate=85/15). In this case, 50 mg (40%) of colorless, crystalline16-dimethyl-8β-vinyl-estra-1,3,5(10)-trien-3,17β-ol with a melting pointof 113-123° C. (decomposition) accumulated.

EXAMPLE 13

[0370]3-methoxy-8β-(prop-1-(E)-enyl)-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene

[0371] A mixture that consists of 4 ml of pentane, 20 ml of1,2-dimethoxyethane and 2 ml of diethylethylphosphonate that was cooledto −78° C. was mixed under argon with 8 ml of a 1.7 M solution oftert-butyllithium (in pentane) and stirred for 15 minutes at thistemperature. Then, a solution that consists of 500 mg of8β-formyl-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienein 8 ml of 1,2-dimethoxyethane and 1.5 ml of pentane was added in drops,stirred for 30 minutes while being exposed to continuous cooling andstirred for 1.5 hours while being heated to room temperature. Then, thepentane was distilled off, and the remaining reaction solution wasrefluxed for 3 hours.

[0372] The mixture was poured onto crushed ice, and the fine whiteprecipitate was filtered off and dried. After a chromatographicpurification on silica gel (solvent mixture: cyclohexane/ethylacetate=20/1), 275 mg (54%) of3-methoxy-8β-(prop-1-(E)-enyl)-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienein the form of a colorless foam was obtained.

[0373] 8β-prop-1-(E)-enyl-estra-1,3,5(10)-triene-3,17β-diol

[0374] 275 mg of3-methoxy-8β-(prop-1-(E)-enyl)-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trienewas reacted according to the general operating instructions for cleavingTHP and 3-methyl ether. The crude8β-prop-1-(E)-enyl-estra-1,3,5(10)-triene-3,17β-diol was obtained in ayield of 108 mg (52%) after apurification on silica gel (solventmixture: cyclohexane/ethyl acetate=8/2) with a melting point of 110-125°C.

EXAMPLE 14

[0375]3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5(10)-triene

[0376] A solution of 80 mg of3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one in 2 ml of THF that wascooled to 0° C. was mixed under argon with 0.2 ml oftrifluoromethyltrimethyl-silane, and 5 mg of tetrabutylammonium fluoridetrihydrate, and it was stirred for 24 hours at room temperature. Thedark reaction solution was poured onto ice-cold water, extracted severaltimes with ethyl acetate, washed with saturated sodium chloridesolution, dried on magnesium sulfate and concentrated by evaporation ina vacuum. The crude product that was obtained was purified by flashchromatography on silica gel (solvent mixture: cyclohexane/ethylacetate=9/1). 63 mg (54%) of3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5(10)-trienewas obtained as a dark oil.

[0377] 17α-trifluoromethyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0378] 1.26 g of tetrabutylammonium fluoride trihydrate was added to asolution of 60 mg of3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5(10)-trienein 6 ml of THF, and it was stirred for 2 hours at room temperature.Then, saturated sodium chloride solution was added, it was extractedseveral times with ethyl acetate, the collected organic phases weredried on magnesium sulfate and concentrated by evaporation in a vacuum.The oily, yellow residue (50 mg) was used in the next stage withoutfurther purification.

[0379] A solution of 50 mg of crude3-methoxy-17α-trifluoromethyl-8β-vinyl-estra-1,3,5(10)-trien-17β-ol in 3ml of dichloromethane that was cooled to −78° C. was mixed under argonin succession with 243 mg of tetrabutylammonium iodide and 0.7 ml of a 1M boron trichloride solution in dichloromethane and stirred for 2 hourswhile being heated to 0° C. Then, the reaction mixture was added indrops to a 5° C. saturated ammonium chloride solution and extractedseveral times with ethyl acetate. The collected organic phases werewashed with saturated sodium chloride solution, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The crude product(90 mg) was purified by chromatography on silica gel (solvent mixture:cyclohexane/ethyl acetate=7/3). 25 mg (52%) of powdery17α-trifluoromethyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol with amelting point of 76-79° C. was obtained.

EXAMPLE 15

[0380]2-fluoro-3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene

[0381] 3 ml of a 1.3 M s-butyllithium solution was added in drops underargon to a solution of 120 mg of3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene in 4ml of THF that was cooled to −78° C., it was stirred for 30 minutes andthen a solution that consists of 650 mg of N-fluorodibenzenesulfonimidein 4 ml of THF was added in drops while being exposed to continuouscooling. The reaction mixture was stirred first for 1 hour at −78° C.then for another 16 hours while being heated to room temperature. Thereaction solution was poured onto ice water, extracted several timeswith ethyl acetate, the collected organic phases were washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The dark, oily crude product(330 mg) was used in the next stage without further purification.

[0382] 2-fluoro-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol

[0383] The oily crude product of the last stage was dissolved in 10 mlof methanol, mixed with 1 ml of water and 250 mg of oxalic aciddihydrate and heated for 1 hour to 60° C.

[0384] For working-up, it was diluted with ethyl acetate, washed insuccession with saturated sodium bicarbonate solution and saturatedsodium chloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The crude product that was obtained wasseparated by chromatography on silica gel (solvent mixture:cyclohexane/ethyl acetate=8/2). The2fluoro-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol that was thusobtained (15 mg, 18%) had a melting point of 67-73° C.

EXAMPLE 16

[0385]3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-trien-2-ol

[0386] 3 ml of a 1.3 M s-butyllithium solution was added in drops underargon to a solution of 120 mg of3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene in 4ml of THF that was cooled to −78° C., it was stirred for 30 minutes andthen 0.5 ml of trimethyl borate was added in one shot. While beingheated to 0° C., it was stirred for 2 hours, then 2 ml of 3N sodiumhydroxide solution and 1 ml of 30% hydrogen peroxide were added andfinally stirred for another 4 hours at room temperature.

[0387] The mixture was diluted with water, saturated sodium hydrogensulfite solution was added, extracted several times withmethyl-tert-butyl ether, the collected organic phases were washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. By chromatography of theevaporation residue on silica gel (solvent mixture: n-hexane/ethylacetate=9:1), 65 mg (52%) of colorless, oily3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-trien-2-olwas obtained.

[0388] 8β-vinyl-estra-1,3,5(10)-triene-2,3,17β-triol

[0389] The oily product of the last stage was dissolved in 3 ml ofmethanol, mixed with 0.3 ml of water and 50 mg of oxalic acid dihydrateand heated for 1 hour to 60° C.

[0390] For working-up, it was diluted with ethyl acetate, washed insuccession with saturated sodium bicarbonate solution and saturatedsodium chloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The yellowish, powdery8β-vinyl-estra-1,3,5(10)-triene-2,3,17β-triol that was thus obtained (38mg, 95%) had a melting point of 82-85° C. (decomposition).

[0391] General Operating Instructions for Cleaving Ether of3-methoxy-17-(tetrahydropyran-2-yloxy)-estratrienes and -tetraenes intothe Corresponding 17-alcohols by Acid

[0392] 1.0 mmol of steroid is dissolved in 22 ml of acetone and stirredwith 1.5 ml of 4N hydrochloric acid for 3 hours at room temperature. If,during this time, conversion is not completed, the solution isadditionally heated for 1.5 hours to 50° C. Then, it is diluted with 20ml of water, extracted several times with dichloromethane, the collectedorganic phases are dried with magnesium sulfate, and the solvent isdistilled off in a rotary evaporator. The crude 17-hydroxyl compoundsthat are produced in this way accumulate as foams and are immediatelyfurther processed.

[0393] General Operating Instructions for Cleaving Ether of3-methoxy-17-(tetrahydropyran-2-yloxy)-estratrienes and -tetraenes intothe Corresponding 3,17-diols with Acid and DIBAH

[0394] 1.0 mmol of steroid is dissolved in 15-20 ml of anhydroustoluene, cooled to 0° C. and mixed carefully with 3.0 ml of DIBAH underargon. The reaction mixture is slowly refluxed and kept at thistemperature for 3.5 hours. Then, in succession, 10 ml of ethanol, 10 mlof ethanol-water mixture (v/v:=1/1) and 10 ml of semi-concentratedhydrochloric acid are carefully added in drops to the solution that iscooled to 0° C., and it is extracted several times with ethyl acetate.The collected organic phases are washed neutral with water, dried withmagnesium sulfate and evaporated to the dry state in a rotaryevaporator. The yields lie between 90 and 99%.

Diagram 1

[0395] Description of the synthesis of 1 in: R. P. Stein, G. C. Buxby,R. C. Smith and H. Smith, “11-Oxygenated Steroids and Process for TheirPreparation,” U.S. Pat. No. 3,491,089, Patented Jan. 20, 1970.

Diagram 3

[0396] [Key:]

[0397] mit 16α-OH oder 16β-OH with 16α-OH or 16β-OH

1. 8β-Substituted estra-1,3,5(10)-triene derivatives of general formulaI

in which R² means a hydrogen atom, a halogen atom; a radical R¹⁸— orR¹⁸—O—, whereby R¹⁸ means a hydrogen atom or a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to6 carbon atoms, a trifluoromethyl group; a group R¹⁹SO₂—O—, in which R¹⁹is an R²⁰R²¹N group, whereby R²⁰ and R²¹, independently of one another,mean a hydrogen atom, a C₁-C₅-alkyl radical, a group C(O)R²², in whichR²² represents an optionally substituted, straight-chain orbranched-chain, saturated or unsaturated in up to three places,optionally partially or completely halogenated hydrocarbon radical withup to 10 carbon atoms, an optionally substituted C₃-C₇-cycloalkylradical, an optionally substituted C₄-C₁₅-cycloalkylalkyl radical or anoptionally substituted aryl, heteroaryl or aralkyl radical, or, togetherwith the N-atom, means a polymethylenimino radical with 4 to 6 C atomsor a morpholino radical; R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or—O—C(O)R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R², whereby in addition an aryl, heteroaryl or aralkylradical can stand for R¹⁸; R⁶ and R⁷ each mean a hydrogen atom ortogether an additional bond; R^(6′) and R^(7′), independently of oneanother, mean a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O—or —R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; R⁸ means a straight-chain or branched-chain,optionally partially or completely halogenated alkyl or alkenyl radicalwith up to 5 carbon atoms, an ethinyl or prop-1-inyl radical; R⁹ means ahydrogen atom, a straight-chain or branched-chain, saturated orunsaturated hydrocarbon radical with up to 5 carbon atoms, or togetherwith R¹¹ means an additional bond; R¹¹ means a hydrogen atom or togetherwith R⁹ or together with R¹² means an additional bond; R^(11′) means ahydrogen atom, a halogen atom, a saturated or unsaturated, optionallypartially or completely halogenated (F, Cl) hydrocarbon radical, whichhas a maximum linear chain length of 4 carbon atoms, or a group—X—R^(18′), in which X is an oxygen or sulfur atom, and R^(18′) is analkyl radical with 1 to 3 carbon atoms; R¹² means a hydrogen atom ortogether with R¹¹ means an additional bond; R¹⁴ means a hydrogen atom ortogether with R¹⁵ means an additional bond; R¹⁵ means a hydrogen atom ortogether with R¹⁴ or together with R¹⁶ means an additional bond; R¹⁶means a hydrogen atom or together with R¹⁵ means an additional bond;R^(15′) and R^(16′), independently of one another, mean a hydrogen atom,a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²²in each case in the meaning that is indicated under R²; R¹⁷ and R^(17′)each mean a hydrogen atom; a hydrogen atom and a halogen atom; ahydrogen atom and a benzyloxy group; a hydrogen atom and a groupR¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²; a groupR¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in allabove cases with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; or R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴,in which R²³ and R²⁴, independently of one another, represent a hydrogenatom and a halogen atom, or together an oxygen atom; excluding thecompounds of general formula I′, in which R³ is a hydroxy, methoxy oracetyl group, and simultaneously R² represents a hydrogen atom, R⁶,R^(6′), R⁷ and R^(7′) in each case represent a hydrogen atom; R⁸represents a methyl group, R⁹ represents a hydrogen atom or R⁹ and R¹¹together represent an additional bond, R^(11′) and R¹² in each caserepresent a hydrogen atom, R¹⁴, R¹⁵, R^(15′), R¹⁶ and R^(16′) in eachcase represent a hydrogen atom, and R¹⁷ and R^(17′) for a β-hydroxygroup and a hydrogen atom; for a β-(2-bromoacetyl)oxy group and ahydrogen atom; for a β-acetyl group and a hydrogen atom; a β-carboxylgroup and a hydrogen atom; or R¹⁷ and R^(17′) together represent anoxygen atom.
 2. Estratrienes of general formula I according to claim 1,in which R² means a hydrogen or halogen atom or a hydroxy group; R³means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹ and R²² ineach case in the meaning that is indicated under R² in claim 1, wherebyin addition an aryl or aralkyl radical can stand for R¹⁸; R⁶ and R⁷ eachmean a hydrogen atom; R^(6′) means a hydrogen atom, a hydroxy group, agroup R²² in the meaning that is indicated under R²; R^(7′) means ahydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², withR¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²;R⁸ means a straight-chain or branched-chain, optionally partially orcompletely halogenated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl- or prop-1-inyl radical; R⁹ means a hydrogen atom ortogether with R¹¹ an additional bond; R¹¹ means a hydrogen atom ortogether with R⁹ an additional bond; R^(11′) means a hydrogen atom, ahalogen atom, a saturated or unsaturated, optionally partially orcompletely halogenated (F, Cl) hydrocarbon radical, which has a maximumlinear chain length of 4 carbon atoms, or a group —X—R^(18′), in which Xis a sulfur atom, and R^(18′) is an alkyl radical with 1 to 3 carbonatoms; R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom; R^(16′)means a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or—R²², with R¹⁸, R¹⁹, and R²² in each case in the meaning that isindicated under R²; R¹⁷ and R^(17′) in each case mean a hydrogen atom; ahydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group;a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²²or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and agroup —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²² in each casein the meaning that is indicated under R²; and R¹⁷ and R^(17′) togethermean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of oneanother, represent a hydrogen atom and a halogen atom, or together anoxygen atom.
 3. Estratrienes of general formula I according to claim 1,in which R² means a hydrogen atom or a fluorine atom or a hydroxy group,R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹, and R²²in each case in the meaning that is indicated under R² in claim 1,whereby in addition an aryl or aralkyl radical can stand for R¹⁸; R⁶ andR⁷ in each case mean a hydrogen atom; R^(6′) means a hydrogen atom or ahydroxy group, R^(7′) means a hydrogen atom, a fluorine or chlorineatom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²² in eachcase in the meaning that is indicated under R²; R⁸ means astraight-chain or branched-chain, optionally partially or completelyfluorinated alkyl or alkenyl radical with up to 5 carbon atoms, anethinyl radical or prop-1-inyl radical; R⁹, independently of oneanother, mean a hydrogen atom or together with R¹¹ an additional bond;R^(11′) means a hydrogen atom, a fluorine or chlorine atom, a saturated,straight-chain or branched-chain C₁-C₄-alkyl group, a group —X—R^(18′),in which X is a sulfur atom and R^(18′) means a saturated,straight-chain or branched-chain C₁-C₃-alkyl group, a chloromethyl orchloroethyl group; R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogenatom; R^(16′) means a hydrogen atom, a fluorine or chlorine atom or agroup R¹⁸—O— or —R²², with R¹⁸ and R²² in each case in the meaning thatis indicated under R²; R¹⁷ and R^(17′) in each case mean a hydrogenatom; a hydrogen atom and a halogen atom; a hydrogen atom and abenzyloxy group; a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ anda group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a groupR¹⁸—O— and a group —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²²in each case in the meaning that is indicated under R²; or R¹⁷ andR^(17′) together mean a group ═CR²³R²⁴, in which R²³ and R²⁴,independently of one another, represent a hydrogen atom and a halogenatom, or together an oxygen atom.
 4. Estratrienes of general formula Iaccording to claim 1, in which R^(6′), R^(7′), R⁹, R¹¹, R¹⁴, R¹⁵,R^(15′) and R¹⁶ in each case stand for a hydrogen atom or R^(6′),R^(7′), R¹⁴, R¹⁵, R^(15′) and R¹⁶ in each case stand for a hydrogen atomand R⁹ and R¹¹ together stand for an additional bond, and all othersubstituents have the meanings that are indicated in claim
 1. 5.Estratrienes of general formula I according to claim 1, which have adouble bond in position 9(11), 14(15) or 15(16) or two double bonds inpositions 9(11) and 14(15) or 15(16).
 6. Estratrienes of general formulaI according to claim 1, in which R¹⁷ and R^(17′) are a group R¹⁸—O— anda group R¹⁸—; a group R¹⁸— and a group —O—C(O)R²², with R¹⁸ and R²² ineach case in the meaning that is indicated under R².
 7. Estratrienes ofgeneral formula I according to claim 6, in which R¹⁷ and R^(17′) are ahydroxy group and a hydrogen atom, a C₁-C₄-alkyl group or C₂-C₄-alkinylgroup.
 8. Estratrienes of general formula I according to claim 7, inwhich R¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a methyl,ethinyl, or prop-1-inyl group.
 9. Estratrienes of general formula Iaccording to claim 1, in which R^(16′) stands for a group R¹⁸—O— orR¹⁹SO₂—O— with R¹⁸ and R¹⁹ in each case in the meaning that is indicatedunder R² in claim 1, R¹⁷ and R^(17′) each stand for a hydrogen atom, andall other substituents can have the meanings that are indicated ingeneral formula I.
 10. Estratrienes of general formula I according toclaim 1, namely 8β-Vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol8β-vinyl-estradiol-3-sulfamate 8β-vinyl-estradiol-3,17-disulfamate8β-vinyl-estradiol-3-(N-acetyl)-sulfamate 8β-vinyl-estrone-3-sulfamate8β-vinyl-estron-3 -acetate 8β-vinyl-estriol 8β-vinyl-estriol-3-sulfamate8β-methyl-estrone-3-sulfamate 8β-methyl-estriol8β-(prop-(Z)-enyl)-estradiol 8β-(n-propyl)-estradiol8β-ethinyl-estradiol17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol8β-methyl-estra-1,3,5(10)-triene-3,17α-diol 8β-vinyl-estradiol-diacetate8β-methyl-estradiol-diacetate 8β-vinyl-estradiol-17-valerianate17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.
 11. Use of 8β-substitutedestra-1,3,5(10)-triene derivatives of general formula I′

in which R² means a hydrogen atom, a halogen atom; a radical R¹⁸— orR¹⁸—O—, whereby R¹⁸ means a hydrogen atom or a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to6 carbon atoms, a trifluoromethyl group; a group R¹⁹SO₂—O—, in which R¹⁹is an R²⁰R²¹N group, whereby R²⁰ and R²¹, independently of one another,mean a hydrogen atom, a C₁-C₅-alkyl radical, a group C(O)R²², in whichR²² represents an optionally substituted, straight-chain orbranched-chain, saturated or unsaturated in up to three places,optionally partially or completely halogenated hydrocarbon radical withup to 10 carbon atoms, an optionally substituted C₃-C₇-cycloalkylradical, an optionally substituted C₄-C₁₅-cycloalkylalkyl radical or anoptionally substituted aryl, heteroaryl or aralkyl radical, or, togetherwith the N-atom, means a polymethylenimino radical with 4 to 6 C atomsor a morpholino radical; R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or—O—C(O)R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R², whereby in addition an aryl, heteroaryl or aralkylradical can stand for R¹⁸; R⁶ and R⁷ each mean a hydrogen atom ortogether an additional bond; R^(6′) and R^(7′), independently of oneanother, mean a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O—or —R²², with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; R⁸ means a straight-chain or branched-chain,optionally partially or completely halogenated alkyl or alkenyl radicalwith up to 5 carbon atoms, an ethinyl or prop-1-inyl radical; R⁹ means ahydrogen atom, a straight-chain or branched-chain, saturated orunsaturated hydrocarbon radical with up to 5 carbon atoms, or togetherwith R¹¹ means an additional bond; R¹¹ means a hydrogen atom or togetherwith R⁹ or together with R¹² means an additional bond; R^(11′) means ahydrogen atom, a halogen atom, a saturated or unsaturated, optionallypartially or completely halogenated (F, Cl) hydrocarbon radical, whichhas a maximum linear chain length of 4 carbon atoms, or a group—X—R^(18′), in which X is an oxygen or sulfur atom, and R^(18′) is analkyl radical with 1 to 3 carbon atoms; R¹² means a hydrogen atom ortogether with R¹¹ means an additional bond; R¹⁴ means a hydrogen atom ortogether with R¹⁵ means an additional bond; R¹⁵ means a hydrogen atom ortogether with R¹⁴ or together with R¹⁶ means an additional bond; R¹⁶means a hydrogen atom or together with R¹⁵ means an additional bond;R^(15′) and R^(16′), independently of one another, mean a hydrogen atom,a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸, R¹⁹ and R²²in each case in the meaning that is indicated under R²; R¹⁷ and R^(17′)each mean a hydrogen atom; a hydrogen atom and a halogen atom; ahydrogen atom and a benzyloxy group; a hydrogen atom and a groupR¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²² or —O—C(O)R²²;a group R¹⁸—O—and a group R¹⁸—; a group R¹⁸—O— and a group —O—C(O)R²², in all abovecases with R¹⁸, R¹⁹ and R²² in each case in the meaning that isindicated under R²; or R¹⁷ and R^(17′) together mean a group ═CR²³R²⁴,in which R²³ and R²⁴, independently of one another, represent a hydrogenatom and a halogen atom, or together an oxygen atom; for treatment ofestrogen-deficiency-induced diseases and conditions in women and in men.12. Use of estratrienes of general formula I′ according to claim 11, inwhich R² means a hydrogen or halogen atom or a hydroxy group; R³ means agroup R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², with R¹⁸, R¹⁹ and R²² in eachcase in the meaning that is indicated under R² in claim 1, whereby inaddition an aryl or aralkyl radical can stand for R¹⁸; R⁶ and R⁷ eachmean a hydrogen atom; R^(6′) means a hydrogen atom, a hydroxy group, agroup R²² in the meaning that is indicated under R²; R^(7′) means ahydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², withR¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R²;R⁸ means a straight-chain or branched-chain, optionally partially orcompletely halogenated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl- or prop-1-inyl radical; R⁹ means a hydrogen atom ortogether with R¹¹ an additional bond; R¹¹ means a hydrogen atom ortogether with R⁹ an additional bond; R^(11′) means a hydrogen atom, ahalogen atom, a saturated or unsaturated, optionally partially orcompletely halogenated (F, Cl) hydrocarbon radical, which has a maximumlinear chain length of 4 carbon atoms, or a group —X—R^(18′), in which Xis a sulfur atom, and R^(18′) is an alkyl radical with 1 to 3 carbonatoms; R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom; R^(16′)means a hydrogen atom, a halogen atom, a group R¹⁸—O—, R¹⁹SO₂—O— or—R²², with R¹⁸, R¹⁹, and R²² in each case in the meaning that isindicated under R²; R¹⁷ and R^(17′) in each case mean a hydrogen atom; ahydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group;a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ and a group —C(O)R²²or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a group R¹⁸—O— and agroup —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²² in each casein the meaning that is indicated under R²; and R¹⁷ and R^(17′) togethermean a group ═CR²³R²⁴, in which R²³ and R²⁴, independently of oneanother, represent a hydrogen atom and a halogen atom, or together anoxygen atom.
 13. Use of estratrienes of general formula I′ according toclaim 11, in which R² means a hydrogen atom or a fluorine atom or ahydroxy group, R³ means a group R¹⁸—O—, R¹⁹SO₂—O— or —O—C(O)R²², withR¹⁸, R¹⁹, and R²² in each case in the meaning that is indicated under R²in claim 1, whereby in addition an aryl or aralkyl radical can stand forR¹⁸; R⁶ and R⁷ in each case mean a hydrogen atom; R^(6′) means ahydrogen atom or a hydroxy group, R^(7′) means a hydrogen atom, afluorine or chlorine atom, a group R¹⁸—O—, R¹⁹SO₂—O— or —R²², with R¹⁸,R¹⁹ and R²² in each case in the meaning that is indicated under R²; R⁸means a straight-chain or branched-chain, optionally partially orcompletely fluorinated alkyl or alkenyl radical with up to 5 carbonatoms, an ethinyl radical or prop-1-inyl radical; R⁹, independently ofone another, mean a hydrogen atom or together with R¹¹ an additionalbond; R^(11′) means a hydrogen atom, a fluorine or chlorine atom, asaturated, straight-chain or branched-chain C₁-C₄-alkyl group, a group—X—R^(18′), in which X is a sulfur atom and R^(18′) means a saturated,straight-chain or branched-chain C₁-C₃-alkyl group, a chloromethyl orchloroethyl group; R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogenatom; R^(16′) means a hydrogen atom, a fluorine or chlorine atom or agroup R¹⁸—O or —R²², with R¹⁸ and R²² in each case in the meaning thatis indicated under R²; R¹⁷ and R^(17′) in each case mean a hydrogenatom; a hydrogen atom and a halogen atom; a hydrogen atom and abenzyloxy group; a hydrogen atom and a group R¹⁹SO₂—O—; a group R¹⁸ anda group —C(O)R²² or —O—C(O)R²²; a group R¹⁸—O— and a group R¹⁸—; a groupR¹⁸—O— and a group —O—C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²²in each case in the meaning that is indicated under R²; or R¹⁷ andR^(17′) together mean a group ═CR²³R²⁴, in which R²³ and R²⁴,independently of one another, represent a hydrogen atom and a halogenatom, or together an oxygen atom.
 14. Use of estratrienes of generalformula I′ according to claim 11, in which R^(6′), R^(7′), R⁹, R¹¹, R¹⁴,R¹⁵, R^(15′) and R¹⁶ in each case stand for a hydrogen atom or R^(6′),R^(7′), R¹⁴, R¹⁵, R^(15′) and R¹⁶ in each case stand for a hydrogen atomand R⁹ and R¹¹ together stand for an additional bond, and all othersubstituents have the meanings that are indicated in claim
 1. 15. Use ofestratrienes of general formula I′ according to claim 11, which have adouble bond in position 9(11), 14(15) or 15(16) or two double bonds inpositions 9(11) and 14(15) or 15(16).
 16. Use of estratrienes of generalformula I′ according to claim 11, in which R¹⁷ and R^(17′) are a groupR¹⁸—O— and a group R¹⁸—; a group R¹⁸— and a group —O—C(O)R²², with R¹⁸and R²² in each case in the meaning that is indicated under R².
 17. Useof estratrienes of general formula I′ according to claim 16, in whichR¹⁷ and R^(17′) are a hydroxy group and a hydrogen atom, a C₁-C₄-alkylgroup or a C₂-C₄-alkinyl group.
 18. Use of estratrienes of generalformula I′ according to claim 17, in which R¹⁷ and R^(17′) are a hydroxygroup and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group. 19.Use of estratrienes of general formula I′ according to claim 11, inwhich R^(16′) stands for a group R¹⁸—O— or R¹⁹SO₂—O— with R¹⁸ and R¹⁹ ineach case in the meaning that is indicated under R² in claim 1, R¹⁷ andR^(17′) each stand for a hydrogen atom, and all other substituents canhave the meanings that are indicated in general formula I.
 20. Use ofestratrienes of general formula I′ according to claim 11, selected fromthe group of compounds8β-Methyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol8β-methyl-estra-1,3,5(10)-triene-3,17β-diol3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11 )-tetraene-3,17β-diol8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol8β-vinyl-estradiol-3-sulfamate 8β-vinyl-estradiol-3,17-disulfamate8β-vinyl-estradiol-3-(N-acetyl)-sulfamate 8β-vinyl-estrone-3-sulfamate8β-vinyl-estron-3-acetate 8β-vinyl-estriol 8β-vinyl-estriol-3-sulfamate8β-methyl-estrone-3-sulfamate 8β-methyl-estriol8β-(prop-(Z)-enyl)-estradiol 8β-(n-propyl)-estradiol8β-ethinyl-estradiol17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol8β-methyl-estra-1,3,5(10)-triene-3,17α-diol 8β-vinyl-estradiol-diacetate8β-methyl-estradiol-diacetate 8β-vinyl-estradiol-17-valerianate17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.
 21. Use according toclaim 11 for treatment of perimenopausal and postmenopausal symptoms.22. Use according to claim 11 for treatment of peri- andpost-male-menopausal symptoms.
 23. Use according to claim 21 forprevention and treatment of hot flashes, sleep disturbances,irritability, mood swings, incontinence, vaginal atrophy, andhormone-deficiency-induced emotional diseases.
 24. Use according toclaim 23 for prevention and treatment of diseases in the urogenitaltract.
 25. Use according to claim 11 for prevention and therapy ofgastrointestinal diseases.
 26. Use according to claim 25 for preventionand therapy of ulcers and hemorrhagic diatheses in the gastrointestinaltract.
 27. Use according to claim 26 for prevention and therapy ofneoplasias.
 28. Use according to claim 11 for in-vitro treatment of maleinfertility.
 29. Use according to claim 11 for in-vivo treatment of maleinfertility.
 30. Use according to claim 11 for in-vitro treatment offemale infertility.
 31. Use according to claim 11 for in-vivo treatmentof female infertility.
 32. Use according to claim 11 for hormonereplacement therapy (HRT).
 33. Use according to claim 11 for the therapyof hormone-deficiency-induced symptoms in the case of surgical,medicinal or ovarian dysfunction that is caused in some other way. 34.Use according to claim 11 for prophylaxis and therapy of ahormone-deficiency-induced bone mass loss.
 35. Use according to claim 34for prophylaxis and therapy of osteoporosis.
 36. Use according to claim11 for prevention and therapy of cardiovascular diseases.
 37. Useaccording to claim 11 for prevention and treatment of vascular diseases.38. Use according to claim 37 for prevention and treatment ofarteriosclerosis.
 39. Use according to claim 37 for prevention andtreatment of neointimal hyperplasias.
 40. Use according to claim 11 forprevention and treatment of hormone-deficiency-induced neurodegenerativediseases.
 41. Use according to claim 11 for prevention and treatment ofAlzheimer's disease as well as hormone-deficiency-induced impairment ofmemory and learning capacity.
 42. Use according to claim 11 fortreatment of inflammatory diseases and diseases of the immune system.43. Use according to claim 11 for prevention and treatment of benignprostate hyperplasia (BPH).
 44. Use of the structural part of formula II(8β-substituted-estra-1,3,5(10)triene structural part)

in which R⁸ represents a straight-chain or branched-chain, optionallypartially or completely halogenated alkyl or alkenyl radical with up to5 carbon atoms, an ethinyl- or prop-1-inyl radical, as a component ofthe total structure of compounds that have in vitro dissociation withrespect to binding to estrogen receptor preparations of rat prostatesand rat uteri.
 45. Use of the structural part of formula II according toclaim 44 as a component of the total structure of compounds that have adissociation in favor of their estrogenic action on bone rather than theuterus.
 46. Use of the structural part of formula II′

according to claim 44 or
 45. 47. Pharmaceutical compositions thatcontain at least one compound according to one of claims 1 to 10 as wellas a pharmaceutically compatible vehicle.